色氨酸代谢及信号通路在肿瘤发生发展中的分子机制与治疗意义

Tryptophan (Trp) metabolism involves three primary pathways: the kynurenine (Kyn) pathway (KP), the 5-hydroxytryptamine (serotonin, 5-HT) pathway, and the indole pathway. Under normal physiological conditions, Trp metabolism plays crucial roles in regulating inflammation, immunity, and neuronal function. Key rate-limiting enzymes such as indoleamine-2,3-dioxygenase (IDO), Trp-2,3-dioxygenase (TDO), and kynurenine monooxygenase (KMO) drive these metabolic processes. Imbalances in Trp metabolism are linked to various cancers and often correlate with poor prognosis and adverse clinical characteristics. Dysregulated Trp metabolism fosters tumor growth and immune evasion primarily by creating an immunosuppressive tumor microenvironment (TME). Activation of the KP results in the production of immunosuppressive metabolites like Kyn, which modulate immune responses and promote oncogenesis mainly through interaction with the aryl hydrocarbon receptor (AHR). Targeting Trp metabolism therapeutically has shown significant potential, especially with the development of small-molecule inhibitors for IDO1, TDO, and other key enzymes. These inhibitors disrupt the immunosuppressive signals within the TME, potentially restoring effective anti-tumor immune responses. Recently, IDO1 inhibitors have been tested in clinical trials, showing the potential to enhance the effects of existing cancer therapies. However, mixed results in later-stage trials underscore the need for a deeper understanding of Trp metabolism and its complex role in cancer. Recent advancements have also explored combining Trp metabolism inhibitors with other treatments, such as immune checkpoint inhibitors, chemotherapy, and radiotherapy, to enhance therapeutic efficacy and overcome resistance mechanisms. This review summarizes the current understanding of Trp metabolism and signaling in cancer, detailing the oncogenic mechanisms and clinical significance of dysregulated Trp metabolism. Additionally, it provides insights into the challenges in developing Trp-targeted therapies and future research directions aimed at optimizing these therapeutic strategies and improving patient outcomes.

Tryptophan (Trp) is an essential amino acid and key intermediate in a range of biological processes. Early studies identified altered Trp utilization in cancer cells favoring cancer survival and growth. Seminal findings linking Trp metabolism and suppression of immunity led to an explosion of interest ultimately culminating in clinical trials targeting these pathways in melanoma. The failure of these trials led to a clinical retreat in this approach; however, recent insights into the complex interplay of the various Trp circuits and between tumor cells, immune cells, and the microbiota have shown that reconsideration of Trp metabolism is needed. Here, we discuss recent developments in our understanding of Trp metabolism and apparent contradictions in the field. We also discuss adaptations that occur when Trp pathways are manipulated, which may impact therapy responses.

… various mechanisms through which tryptophan metabolites … A study on tryptophan metabolism in bladder cancer patients … of them had abnormal tryptophan metabolism. Similar studies …

Abstract Tumours utilise tryptophan (Trp) and its metabolites to promote their growth and evade host defences. They recruit Trp through up-regulation of Trp transporters, and up-regulate key enzymes of Trp degradation and down-regulate others. Thus, Trp 2,3-dioxygenase (TDO2), indoleamine 2,3-dioxygenase 1 (IDO1), IDO2, N′-formylkynurenine formamidase (FAMID) and Kyn aminotransferase 1 (KAT1) are all up-regulated in many cancer types, whereas Kyn monooxygenase (KMO), kynureninase (KYNU), 2-amino-3-carboxymuconic acid-6-semialdehyde decarboxylase (ACMSD) and quinolinate phosphoribosyltransferase (QPRT) are up-regulated in a few, but down-regulated in many, cancers. This results in accumulation of the aryl hydrocarbon receptor (AhR) ligand kynurenic acid and in depriving the host of NAD+ by blocking its synthesis from quinolinic acid. The host loses more NAD+ by up-regulation of the NAD+-consuming poly (ADP-ribose) polymerases (PARPs) and the protein acetylaters SIRTs. The nicotinamide arising from PARP and SIRT activation can be recycled in tumours to NAD+ by the up-regulated key enzymes of the salvage pathway. Up-regulation of the Trp transporters SLC1A5 and SLC7A5 is associated mostly with that of TDO2 = FAMID > KAT1 > IDO2 > IDO1. Tumours down-regulate enzymes of serotonin synthesis, thereby removing competition for Trp from the serotonin pathway. Strategies for combating tumoral immune escape could involve inhibition of Trp transport into tumours, inhibition of TDO and IDOs, inhibition of FAMID, inhibition of KAT and KYNU, inhibition of NMPRT and NMNAT, inhibition of the AhR, IL-4I1, PARPs and SIRTs, and by decreasing plasma free Trp availability to tumours by albumin infusion or antilipolytic agents and inhibition of glucocorticoid induction of TDO by glucocorticoid antagonism.

Tryptophan (Trp) metabolism is associated with diverse biological processes, including nerve conduction, inflammation, and the immune response. The majority of free Trp is broken down through the kynurenine (Kyn) pathway (KP), in which indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO) catalyze the rate-limiting step. Clinical studies have demonstrated that Trp metabolism promotes tumor progression due to modulation of the immunosuppressive microenvironment through multiple mechanisms. In this process, IDO-expressing dendritic cells (DCs) exhibit tolerogenic potential and orchestrate T cell immune responses. Various signaling molecules control IDO expression, initiating the immunoregulatory pathway of Trp catabolism. Based on these characteristics, KP enzymes and catabolites are emerging as significant prognostic indicators and potential therapeutic targets of cancer. The physiological and oncologic roles of Trp metabolism are briefly summarized here, along with great challenges for treatment strategies.

Tryptophan (Trp) metabolism is a complex and important biochemical process in humans. It is vital in protein synthesis and is a precursor of various bioactive molecules. Trp is metabolized through the kynurenine, serotonin and indole pathways, mediating diverse physiological functions, including neurotransmitter synthesis, immune regulation, antioxidant effects, and biosynthesis of niacin and melatonin. These metabolic pathways maintain essential functions under normal physiological conditions. However, they are significantly affected by various types of cancers. Trp metabolites regulate tumor angiogenesis, affect the self-renewal of cancer stem cells, and participate in immune evasion and cell death through complex mechanisms. As the mechanisms underlying Trp metabolism in diseases are increasingly being elucidated, targeting Trp metabolic pathways has emerged as a promising therapeutic strategy. Further investigation of the molecular mechanisms underlying Trp metabolism and its role in diseases may provide new perspectives and approaches for diagnosing and treating diseases.

… and mechanisms of Kyn import into cancer cells is needed. Correlations between Trp transporters and Trp-metabolizing enzymes with cancer … In summary, the field of Trp metabolism is …

Tryptophan (Trp) metabolism primarily involves the kynurenine, 5-hydroxytryptamine, and indole pathways. A variety of bioactive compounds produced via Trp metabolism can regulate various physiological functions, including inflammation, metabolism, immune responses, and neurological function. Emerging evidence supports an intimate relationship between Trp metabolism disorder and diseases. The levels or ratios of Trp metabolites are significantly associated with many clinical features. Additionally, studies have shown that disease progression can be controlled by modulating Trp metabolism. Indoleamine-2,3-dioxygenase, Trp-2,3-dioxygenase, kynurenine-3-monooxygenase, and Trp hydroxylase are the rate-limiting enzymes that are critical for Trp metabolism. These key regulatory enzymes can be targeted for treating several diseases, including tumors. These findings provide novel insights into the treatment of diseases. In this review, we have summarized the recent research progress on the role of Trp metabolites in health and disease along with their clinical applications.

Abstract: Intracellular tryptophan (Trp) is catabolized to a large repertoire of metabolites via two major pathways: indoleamine and tryptophan 2, 3-dioxygenases (IDO/TDO) and Trp hydroxylase (TPH) pathways. The catabolites possess diverse biological activities and carry out various physiological functions. Several catabolites such as kynurenine (Kyn) and serotonin promote while melatonin and 5-methoxytryptophan (5-MTP) suppress cancer growth and metastasis. Cancer cell-derived Kyn enhances cancer growth and evasion of immunosurveillance by interacting with cancer cell and immune cell membrane aryl hydrocarbon receptors (AHR), respectively. Serotonin exerts its tumor-promoting activities through type 1 and type 2 serotonin receptors. 5-MTP and melatonin suppress cancer growth and metastasis by common mechanisms, i.e., inhibition of p300 histone acetyltransferase (HAT) and NF-κB activation, and suppression of cyclooxygenase-2 and cytokine transcription. Both metabolites block p38 MAPK signaling pathway. Human cancer tissues express increased levels of IDO, TDO and kynurenine monooxygenase (KMO) which are correlated with reduced patient survival. In summary, cancer Trp metabolism regulates cancer growth and metastasis by complex mechanisms. 5-MTP and melatonin provide valuable lead to develop new drugs for chemo-prevention and adjuvant therapy of cancer.

… to attack and clear the cancer. Tryptophan metabolism along the kynurenine pathway (KP) is a … Herein, we provide an in-depth review of how tryptophan metabolism and KP metabolites …

Tryptophan (Trp) metabolism plays a crucial role in influencing the development of digestive system tumors. Dysregulation of Trp and its metabolites has been identified in various digestive system cancers, including esophageal, gastric, liver, colorectal, and pancreatic cancers. Aberrantly expressed Trp metabolites are associated with diverse clinical features in digestive system tumors. Moreover, the levels of these metabolites can serve as prognostic indicators and predictors of recurrence risk in patients with digestive system tumors. Trp metabolites exert their influence on tumor growth and metastasis through multiple mechanisms, including immune evasion, angiogenesis promotion, and drug resistance enhancement. Suppressing the expression of key enzymes in Trp metabolism can reduce the accumulation of these metabolites, effectively impacting their role in the promotion of tumor progression and metastasis. Strategies targeting Trp metabolism through specific enzyme inhibitors or tailored drugs exhibit considerable promise in enhancing therapeutic outcomes for digestive system tumors. In addition, integrating these approaches with immunotherapy holds the potential to further enhance treatment efficacy.

Based on its effects on both tumour cell intrinsic malignant properties as well as anti-tumour immune responses, tryptophan catabolism has emerged as an important metabolic regulator of cancer progression. Three enzymes, indoleamine-2,3-dioxygenase 1 and 2 (IDO1/2) and tryptophan-2,3-dioxygenase (TDO2), catalyse the first step of the degradation of the essential amino acid tryptophan (Trp) to kynurenine (Kyn). The notion of inhibiting IDO1 using small-molecule inhibitors elicited high hopes of a positive impact in the field of immuno-oncology, by restoring anti-tumour immune responses and synergising with other immunotherapies such as immune checkpoint inhibition. However, clinical trials with IDO1 inhibitors have yielded disappointing results, hence raising many questions. This review will discuss strategies to target Trp-degrading enzymes and possible down-stream consequences of their inhibition. We aim to provide comprehensive background information on Trp catabolic enzymes as targets in immuno-oncology and their current state of development. Details of the clinical trials with IDO1 inhibitors, including patient stratification, possible effects of the inhibitors themselves, effects of pre-treatments and the therapies the inhibitors were combined with, are discussed and mechanisms proposed that might have compensated for IDO1 inhibition. Finally, alternative approaches are suggested to circumvent these problems.

Serotonin signaling has been associated with tumorigenesis and tumor progression. Targeting the serotonin transporter to block serotonin cellular uptake confers antineoplastic effects in various tumors, including colon cancer. However, the antineoplastic mechanism of serotonin transporter inhibition and serotonin metabolism alterations in the absence of serotonin transporter have not been elucidated, especially in colon cancer, which might limit anti-tumor effects associating with targeting serotonin transporter. The promotion in the uptake and catabolism of extracellular tryptophan and targeting serotonin transporter was detected by using quantitative reverse-transcription polymerase chain reaction, western blotting and liquid chromatography tandem mass spectrometry. Western blotting Immunoprecipitation and immunofluorescence was utilized to research the serotonylation of mTOR by serotonin and serotonin transporter inhibition. The primary mouse model, homograft model and tissue microarry was used to explore the tryptophan pathway in colon cancer. The cell viability assay, western blotting, xenograft and primary colon cancer mouse model were used to identify whether the combination of sertraline and tryptophan restriction had a synergistic effect. Targeting serotonin transporter through genetic ablation or pharmacological inhibition in vitro and in vivo induced a compensatory effect by promoting the uptake and catabolism of extracellular tryptophan in colon cancer. Mechanistically, targeting serotonin transporter suppressed mTOR serotonylation, leading to mTOR inactivation and increased tryptophan uptake. In turn, this process promoted serotonin biosynthesis and oncogenic metabolite kynurenine production through enhanced tryptophan catabolism. Tryptophan deprivation, or blocking its uptake by using trametinib, a MEK inhibitor, can sensitize colon cancer to selective serotonin reuptake inhibitors. The present study elucidated a novel feedback mechanism involved in the regulation of serotonin homeostasis and suggested innovative strategies for selective serotonin reuptake inhibitors-based treatment of colon cancer.

Tryptophan catabolism in cancer is increasingly being recognized as an important microenvironmental factor that suppresses antitumor immune responses. It has been proposed that the essential amino acid tryptophan is catabolized in the tumor tissue by the rate-limiting enzyme indoleamine-2,3-dioxygenase (IDO) expressed in tumor cells or antigen-presenting cells. This metabolic pathway creates an immunosuppressive milieu in tumors and in tumor-draining lymph nodes by inducing T-cell anergy and apoptosis through depletion of tryptophan and accumulation of immunosuppressive tryptophan catabolites. Competitive inhibitors of IDO are currently being tested in clinical trials in patients with solid cancer, with the aim of enhancing the efficacy of conventional chemotherapy. There are, however, certain tumor types that are capable of catabolizing tryptophan but are largely IDO-negative. Recent evidence from studies in malignant gliomas and other types of cancers points to alternative enzymatic pathways of tryptophan catabolism involving tryptophan-2,3-dioxygenase (TDO). TDO, which is considered responsible for regulating systemic tryptophan levels in the liver, is constitutively expressed in some cancers and is equally capable of suppressing antitumor immune responses. Depletion of tryptophan induces signaling events in T cells, leading to anergy and apoptosis; however, active immunomodulation by accumulating tryptophan catabolites, most notably kynurenine, appears to play an equally important role. These immunomodulatory effects of kynurenine are mediated by the aryl hydrocarbon receptor. This intracellular transcription factor has classically been viewed as a receptor for environmental toxins, such as dioxin, and its important role in influencing immune responses, especially in epithelial barriers, is only beginning to emerge. This review summarizes the exciting developments in our understanding of tryptophan catabolism as a key factor in the immunobiology of cancer. Cancer Res; 72(21); 5435–40. ©2012 AACR.

The activation of the kynurenine pathway in cancer progression and metastasis through immunomodulatory pathways has drawn attention to the potential for kynurenine pathway inhibition. The activation of the kynurenine pathway, which results in the production of kynurenine metabolites through the degradation of tryptophan, promotes the development of intrinsically malignant properties in cancer cells while facilitating tumour immune escape. In addition, kynurenine metabolites act as biologically active substances to promote cancer development and metastasis.

ABSTRACT Tryptophan (Trp) is an essential amino acid that serves as a precursor for the synthesis of several important bioactive compounds. Trp is involved in a variety of pathophysiological processes, including neuronal function, metabolism, inflammatory responses, oxidative stress, immune regulation, and intestinal homeostasis. The role of Trp metabolism in tumorigenesis and cancer progression is of particular significance. The influence of Trp and its metabolites on tumor growth and metastasis is mediated through various mechanisms, such as immune evasion, promotion of angiogenesis, and increased resistance to therapeutic agents. This review presents the physiological pathways involved in Trp metabolism and its implications for various malignancies. We also highlight the latest clinical research targeting Trp metabolic pathways in oncology, in addition to exploring future directions for therapeutic advancements aimed at modulating Trp metabolism to enhance cancer treatment outcomes.

Amino acids are fundamental units of molecular components that are essential for sustaining life; however, their metabolism is closely interconnected to the control systems of cell function. Tryptophan (Trp) is an essential amino acid catabolized by complex metabolic pathways. Several of the resulting Trp metabolites are bioactive and play central roles in physiology and pathophysiology. Additionally, various physiological functions of Trp metabolites are mutually regulated by the gut microbiota and intestine to coordinately maintain intestinal homeostasis and symbiosis under steady state conditions and during the immune response to pathogens and xenotoxins. Cancer and inflammatory diseases are associated with dysbiosis- and host-related aberrant Trp metabolism and inactivation of the aryl hydrocarbon receptor (AHR), which is a receptor of several Trp metabolites. In this review, we focus on the mechanisms through which Trp metabolism converges to AHR activation for the modulation of immune function and restoration of tissue homeostasis and how these processes can be targeted using therapeutic approaches for cancer and inflammatory and autoimmune diseases.

Our study provides a detailed exploration of the role of tryptophan metabolism in pancreatic cancer, including its normal function, the impact of targeted drugs, and the influence of gut microbiota on metabolism. Additionally, the article discusses how tryptophan metabolism affects early diagnosis, immune microenvironment, metastasis and proliferation, and pharmaceutical interventions in pancreatic cancer. Research has found that tryptophan and its metabolites can serve as potential biomarkers for early diagnosis and may improve the prognosis of pancreatic cancer patients by modulating the tumor immune microenvironment.

Blockade of the immunosuppressive tryptophan catabolism mediated by indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) holds enormous promise for sensitising cancer patients to immune checkpoint blockade. Yet, only IDO1 inhibitors had entered clinical trials so far, and those agents have generated disappointing clinical results. Improved understanding of molecular mechanisms involved in the immune-regulatory function of the tryptophan catabolism is likely to optimise therapeutic strategies to block this pathway. The immunosuppressive role of tryptophan metabolite kynurenine is becoming increasingly clear, but it remains a mystery if tryptophan exerts functions beyond serving as a precursor for kynurenine. Here we hypothesise that tryptophan acts as a rheostat of kynurenine-mediated immunosuppression by competing with kynurenine for entry into immune T-cells through the amino acid transporter called System L. This hypothesis stems from the observations that elevated tryptophan levels in TDO-knockout mice relieve immunosuppression instigated by IDO1, and that the vacancy of System L transporter modulates kynurenine entry into CD4+ T-cells. This hypothesis has two potential therapeutic implications. Firstly, potent TDO inhibitors are expected to indirectly inhibit IDO1 hence development of TDO-selective inhibitors appears advantageous compared to IDO1-selective and dual IDO1/TDO inhibitors. Secondly, oral supplementation with System L substrates such as leucine represents a novel potential therapeutic modality to restrain the immunosuppressive kynurenine and restore anti-tumour immunity.

The tryptophan (TRP) to kynurenine (KYN) metabolic pathway is now firmly established as a key regulator of innate and adaptive immunity. A plethora of preclinical models suggests that this immune tolerance pathway – driven by the key and rate-limiting enzymes indoleamine-2,3-dioxygenase and TRP-2,3-dioxygenase – is active in cancer immunity, autoimmunity, infection, transplant rejection, and allergy. Drugs targeting this pathway, specifically indoleamine-2,3-dioxygenase, are already in clinical trials with the aim at reverting cancer-induced immunosuppression. In the past years, there has been an increase in our understanding of the regulation and downstream mediators of TRP metabolism, such as the aryl hydrocarbon receptor as a receptor for KYN and kynurenic acid. This more detailed understanding will expand our opportunities to interfere with the pathway therapeutically on multiple levels. Here, we discuss the perspective of targeting TRP metabolism at these different levels based on reviewing recent insight into the regulation of TRP metabolism and its downstream effectors.

Kynurenine (Kyn) pathway is a significant metabolic pathway of tryptophan (Trp). The metabolites of the Kyn pathway are closely correlated with numerous diseases. Two main enzymes, indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO or TDO2), regulate the first and rate-limiting step of the Kyn pathway. These enzymes are directly or indirectly involved in various diseases, including inflammatory diseases, cancer, diabetes, and mental disorders. Presently, an increasing number of potential mechanisms have been revealed. In the present review, we depict the structure of IDO and TDO and explicate their functions in various diseases to facilitate a better understanding of them and to indicate new therapeutic plans to target them. Moreover, we summarize the inhibitors of IDO/TDO that are currently under development and their efficacy in the treatment of cancer and other diseases.

Background The impact of non-small cell lung cancer (NSCLC) metabolism on the immune microenvironment is not well understood within platinum resistance. We have identified crucial metabolic differences between cisplatin-resistant (CR) and cisplatin-sensitive (CS) NSCLC cells with elevated indoleamine 2,3-dioxygenase-1 (IDO1) activity in CR, recognized by increased kynurenine (KYN) production. Methods Co-culture, syngeneic, and humanize mice models were utilized. C57BL/6 mice were inoculated with either Lewis lung carcinoma mouse cells (LLC) or their platinum-resistant counterpart (LLC-CR) cells. Humanized mice were inoculated with either A (human CS cells) or ALC (human CR cells). Mice were treated with either IDO1 inhibitor or TDO2 (tryptophan 2,3-dioxygenase-2) inhibitor at 200 mg/kg P.O. once a day for 15 days; or with a new-in-class, IDO1/TDO2 dual inhibitor AT-0174 at 170 mg/kg P.O. once a day for 15 days with and without anti-PD1 antibody (10 mg/kg, every 3 days). Immune profiles and KYN and tryptophan (TRP) production were evaluated. Results CR tumors exhibited a more highly immunosuppressive environment that debilitated robust anti-tumor immune responses. IDO1-mediated KYN production from CR cells suppressed NKG2D on immune effector natural killer (NK) and CD8^+ T cells and enhanced immunosuppressive populations of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Importantly, while selective IDO1 inhibition attenuated CR tumor growth, it concomitantly upregulated the TDO2 enzyme. To overcome the compensatory induction of TDO2 activity, we employed the IDO1/TDO2 dual inhibitor, AT-0174. Dual inhibition of IDO1/TDO2 in CR mice suppressed tumor growth to a greater degree than IDO1 inhibition alone. Significant enhancement in NKG2D frequency on NK and CD8^+ T cells and a reduction in Tregs and MDSCs were observed following AT-1074 treatment. PD-L1 (programmed death-ligand-1) expression was increased in CR cells; therefore, we assessed dual inhibition + PD1 (programmed cell death protein-1) blocking and report profound anti-tumor growth and improved immunity in CR tumors which in turn extended overall survival in mice. Conclusion Our study reports the presence of platinum-resistant lung tumors that utilize both IDO1/TDO2 enzymes for survival, and to escape immune surveillance as a consequence of KYN metabolites. We also report early in vivo data in support of the potential therapeutic efficacy of the dual IDO1/TDO2 inhibitor AT-0174 as a part of immuno-therapeutic treatment that disrupts tumor metabolism and enhances anti-tumor immunity.

Tryptophan catabolism contributes to tumor immune escape, so inhibiting it could improve antitumor immune therapies. Response to immune checkpoint blockade is enhanced when used with the TDO inhibitor PF06845102/EOS200809 or when administered to TDO-KO mice. Tryptophan 2,3-dioxygenase (TDO) is an enzyme that degrades tryptophan into kynurenine and thereby induces immunosuppression. Like indoleamine 2,3-dioxygenase (IDO1), TDO is considered as a relevant drug target to improve the efficacy of cancer immunotherapy. However, its role in various immunotherapy settings has not been fully characterized. Here, we described a new small-molecule inhibitor of TDO that can modulate kynurenine and tryptophan in plasma, liver, and tumor tissue upon oral administration. We showed that this compound improved the ability of anti-CTLA4 to induce rejection of CT26 tumors expressing TDO. To better characterize TDO as a therapeutic target, we used TDO-KO mice and found that anti-CTLA4 or anti-PD1 induced rejection of MC38 tumors in TDO-KO, but not in wild-type mice. As MC38 tumors did not express TDO, we related this result to the high systemic tryptophan levels in TDO-KO mice, which lack the hepatic TDO needed to contain blood tryptophan. The antitumor effectiveness of anti-PD1 was abolished in TDO-KO mice fed on a tryptophan-low diet that normalized their blood tryptophan level. MC38 tumors expressed IDO1, which could have limited the efficacy of anti-PD1 in wild-type mice and could have been overcome in TDO-KO mice due to the high levels of tryptophan. Accordingly, treatment of mice with an IDO1 inhibitor improved the efficacy of anti-PD1 in wild-type, but not in TDO-KO, mice. These results support the clinical development of TDO inhibitors to increase the efficacy of immunotherapy of TDO-expressing tumors and suggest their effectiveness even in the absence of tumoral TDO expression. See article by Hoffmann et al., p. 19

Tumoral immune escape is an obstacle to successful cancer therapy. Tryptophan (Trp) metabolites along the kynurenine pathway induce immunosuppression involving apoptosis of effector immune cells, which tumors use to escape an immune response. Production of these metabolites is initiated by indoleamine 2,3‐dioxygenase (IDO1). IDO1 inhibitors, however, do not always overcome the immune escape and another enzyme expressed in tumors, Trp 2,3‐dioxygenase (TDO2), has been suggested as the reason. However, without Trp, tumors cannot achieve an immune escape through either enzyme. Trp is therefore key to immune escape. In this perspective paper, Trp availability to tumors will be considered and strategies limiting it proposed. One major determinant of Trp availability is the large increase in plasma free (non‐albumin‐bound) Trp in cancer patients, caused by the low albumin and the high non‐esterified fatty acid (NEFA) concentrations in plasma. Albumin infusions, antilipolytic therapy or both could be used, if indicated, as adjuncts to immunotherapy and other therapies. Inhibition of amino acid uptake by tumors is another strategy and α‐methyl‐DL‐tryptophan or other potential inhibitors could fulfill this role. Glucocorticoid receptor antagonists may have a role in preventing glucocorticoid induction of TDO in host liver and tumors expressing it and in undermining the permissive effect of glucocorticoids on IDO1 induction by cytokines. Nicotinamide may be a promising TDO2 inhibitor lacking disadvantages of current inhibitors. Establishing the Trp disposition status of cancer patients and in various tumor types may provide the information necessary to formulate tailored therapeutic approaches to cancer immunotherapy that can also undermine tumoral immune escape.

Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzing the conversion of tryptophan (Trp) to kynurenine (Kyn) in kynurenine pathway (KP) is involved in the immunosuppression in pancreatic cancer (PC), but the value of IDO1 as an independent prognostic marker for PC is uncertain. Moreover, the correlation between tryptophan 2,3-dioxygenase (TDO), an isozyme of IDO1, and PC is largely unknown. Using TCGA database, the correlation between IDO1 and/or TDO expression and PC patients' survival was analyzed. The expressions of IDO1 and TDO in PC cells and PC mice were examined. The effects of IDO1, TDO or dual inhibition on IDO1 and TDO effector pathway (Aryl hydrocarbon receptor, AhR) and on migration and invasion of PC cells were investigated. The block effect of IDO1/TDO dual inhibitor RY103 on KP was evaluated. The preclinical efficacy of RY103 and its immunomodulatory effect on KPIC orthotopic PC mice and Pan02 tumor-bearing mice were explored. Results showed that IDO1/TDO co-expression is an independent prognostic marker for PC. RY103 can significantly block KP and target Kyn-AhR pathway to blunt the migration and invasion of PC cells, exhibit preclinical efficacy and ameliorate IDO1/TDO-mediated immunosuppression in PC mice.

Indoleamine 2, 3-dioxygenase 1 (IDO1), IDO2, and tryptophan 2, 3-dioxygenase (TDO) comprise a family of enzymes that catalyze the first- and rate-limiting step associated with the catabolic conversion of tryptophan (Trp) into kynurenine (Kyn). Through subsequent enzymatic and spontaneous reactions, Kyn is further converted into the energetic substrates, NAD+ and ATP, to fuel cellular metabolic functions. Coincidently, the depletion of Trp and accumulation of Kyn has been demonstrated to induce effector T-cell apoptosis/dysfunction and immunosuppressive regulatory T-cell induction, respectively. Similar to other immune checkpoints, IDO1 and TDO are suggested to be important targets for immunotherapeutic intervention. This is represented by the recent growth of efforts to inhibit the Trp-to-Kyn pathway as a means to control immunosuppression. Inhibitors currently in clinical trials, INCB024360, GDC-0919, indoximod, and an IDO1 peptide-based vaccine, are being evaluated for their efficacy against a wide range of cancers including melanoma, glioblastoma, non–small cell lung, pancreatic, and/or breast cancer, as well as metastatic disease. Despite the rapid development of potent clinical grade inhibitors, strategic questions remain. Here, we review the state of the literature with respect to current therapeutic inhibitors of tryptophan catabolism, evaluation of those efforts preclinically and clinically, compensatory changes that occur with therapeutic targeting, as well as newly recognized signaling features that raise critical questions to the field. Given the rapidly evolving interest in determining how IDO1/TDO, and to an unknown extent, IDO2, can be targeted for increasing cancer immunotherapeutic efficacy, we present a brief but comprehensive analysis that addresses critical questions, while highlighting the mechanics that remain to be explored. Clin Cancer Res; 21(24); 5427–33. ©2015 AACR.

… Notably, although IDO1 and TDO are expressed at a high level in many cancer subtypes, a … STING-mediated IDO1 induction in the setting of tumor immune evasion and tumor …

Indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO) inhibitors are promising avenues in cancer immunotherapy. These enzymes are key regulators in the kynurenine pathway. modulating immune responses and enabling tumor immune evasion. By targeting IDO and TDO. Therapeutic approaches aim to restore immune surveillance and enhance antitumor activity. This review examines the mechanisms of IDO/TDO in cancer etiology, their consequences in the tumor microenvironment, and the therapeutic development of inhibitors currently being studied. Among these, medications like Indoximod, Epacadostat, and Navoximod have shown promise in influencing the immune system and slowing tumor progression, while dual inhibitors like HTI-1090 try to address broader metabolic connections. Despite tremendous progress, obstacles like tumor heterogeneity, off-target consequences, and varying patient responses remain. The use of IDO/TDO inhibitors with conventional anticancer medications demonstrates their potential to reshape cancer treatment paradigms, contingent on further research to optimize efficacy and safety. Clinical Trial Registration: https://clinicaltrials.gov/study/NCT03844438.

Simple Summary Recently, mechanisms that lead to immune escape by cancer cells have been under great investigation. Elements involved in the tryptophan metabolism pathway and its derivatives are considered factors that play a wide role in silencing the immune system. However, it seems that those agents contribute to tumorigenesis through a direct impact on cancer cells. This study aimed to gather available data about the kynurenine pathway and its modulating effects on disease development through the impact on immune and cancer cells. This allows for an understanding of the complexity of this metabolic pathway in the context of carcinogenesis and indicates ambiguities that may explain the current failure of therapy with the use of compounds inhibiting tryptophan metabolism. The collected data not only help us to understand the pathogenesis of cancer but also provide the basis for the development of new therapeutic strategies in oncology. Abstract Background: The recently discovered phenomenon that cancer cells can avoid immune response has gained scientists’ interest. One of the pathways involved in this process is tryptophan (TRP) metabolism through the kynurenine pathway (KP). Individual components involved in TRP conversion seem to contribute to cancerogenesis both through a direct impact on cancer cells and the modulation of immune cell functionality. Due to this fact, this pathway may serve as a target for immunotherapy and attempts are being made to create novel compounds effective in cancer treatment. However, the results obtained from clinical trials are not satisfactory, which raises questions about the exact role of KP elements in tumorigenesis. An increasing number of experiments reveal that TRP metabolites may either be tumor promoters and suppressors and this is why further research in this field is highly needed. The aim of this study is to present KP as a modulator of cancer development through multiple mechanisms and to point to its ambiguity, which may be a reason for failures in treatment based on the inhibition of tryptophan metabolism

Strategies for unlocking immunosuppression in the tumor microenvironment have been investigated to overcome resistance to first-generation immune checkpoint blockade with anti- programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) agents. Indoleamine 2,3-dioxygenase (IDO) 1, an enzyme catabolizing tryptophan to kynurenine, creates an immunosuppressive environment in preclinical studies. Early phase clinical trials investigating inhibition of IDO1, especially together with checkpoint blockade, provided promising results. Unfortunately, the phase 3 trial of the IDO1 inhibitor epacadostat combined with the PD-1 inhibitor pembrolizumab did not show clinical benefit when compared with pembrolizumab monotherapy in patients with advanced malignant melanoma, which dampened enthusiasm for IDO inhibitors. Even so, several molecules, such as the aryl hydrocarbon receptor and tryptophan 2,3-dioxygenase, were reported as additional potential targets for the modulation of the tryptophan pathway, which might enhance clinical effectiveness. Furthermore, the combination of IDO pathway blockade with agents inhibiting other signals, such as those generated by PIK3CA mutations that may accompany IDO1 upregulation, may be a novel way to enhance activity. Importantly, IDO1 expression level varies by tumor type and among patients with the same tumor type, suggesting that patient selection based on expression levels of IDO1 may be warranted in clinical trials.

… the tumoral immune response and cause tumor immune escape. … of TDO is different in distinct tumors and that TDO and IDO are … of the same tumor, implying that IDO and TDO are not …

Indoleamine 2, 3-dioxygenase 1 (IDO; IDO1; INDO) is a rate-limiting enzyme that metabolizes the essential amino acid, tryptophan, into downstream kynurenines. Canonically, the metabolic depletion of tryptophan and/or the accumulation of kynurenine is the mechanism that defines how immunosuppressive IDO inhibits immune cell effector functions and/or facilitates T cell death. Non-canonically, IDO also suppresses immunity through non-enzymic effects. Since IDO targeting compounds predominantly aim to inhibit metabolic activity as evidenced across the numerous clinical trials currently evaluating safety/efficacy in patients with cancer, in addition to the recent disappointment of IDO enzyme inhibitor therapy during the phase III ECHO-301 trial, the issue of IDO non-enzyme effects have come to the forefront of mechanistic and therapeutic consideration(s). Here, we review enzyme-dependent and -independent IDO-mediated immunosuppression as it primarily relates to glioblastoma (GBM); the most common and aggressive primary brain tumor in adults. Our group's recent discovery that IDO levels increase in the brain parenchyma during advanced age and regardless of whether GBM is present, highlights an immunosuppressive synergy between aging-increased IDO activity in cells of the central nervous system that reside outside of the brain tumor but collaborate with GBM cell IDO activity inside of the tumor. Because of their potential value for the in vivo study of IDO, we also review current transgenic animal modeling systems while highlighting three new constructs recently created by our group. This work converges on the central premise that maximal immunotherapeutic efficacy in subjects with advanced cancer requires both IDO enzyme- and non-enzyme-neutralization, which is not adequately addressed by available IDO-targeting pharmacologic approaches at this time.

Benzo[a]pyrene (BaP) is a toxic polycyclic aromatic hydrocarbon known as an exogenous AhR ligand. This study investigates the role of BaP in inducing immune checkpoint expression in lung adenocarcinoma (LUAD) and the underlying mechanisms involving the aryl hydrocarbon receptor (AhR) and tryptophan (Trp) metabolism. We assessed the expression of immune checkpoint molecules, including PD-L1 and ICOSL, in lung epithelial cell lines (BEAS-2B and H1975) exposed to BaP. The involvement of AhR in BaP-induced immune checkpoint expression was examined using AhR silencing (siAhR). Additionally, the role of Trp metabolism in BaP-mediated immune evasion was explored through culturing in Trp (-/+) condition media, treatments with the inhibitors of rate-limiting enzymes in Trp metabolism (TDO2 and IDO1) and analyses of Trp-catabolizing enzymes. The therapeutic potential of targeting Trp metabolism, specifically TDO2, was evaluated in vivo using C57BL/6 mice orthotopically inoculated with LUAD cells. BaP exposure significantly upregulated the mRNA and surface expression of PD-L1 and ICOSL, with AhR playing a crucial role in this induction. Trp metabolism was found to enhance BaP-mediated immune evasion, as indicated by stronger induction of immune checkpoints in Trp (+) media and the upregulation of Trp-catabolizing enzymes. TDO2 inhibition markedly suppressed the surface expression of PD-L1 and ICOSL, demonstrating the importance of Trp metabolism in BaP-induced immune evasion. Further analysis confirmed the high TDO2 expression in lung adenocarcinoma and its association with poor patient survival. Using an orthotopic implantation mouse model, we demonstrated the inhibitory effect of two different TDO2 inhibitors on tumorigenesis, immune checkpoints, and tryptophan metabolism. This study highlights the key mechanisms behind BaP-induced immune evasion in LUAD, particularly through the TDO2/AhR axis. It reveals how TDO2 inhibitors can counteract immune checkpoint activation and boost anti-tumor immunity, suggesting new paths for targeted lung cancer immunotherapy. The findings significantly improve our understanding of immune evasion in LUAD and underscore the therapeutic promise of TDO2 inhibition.

Tryptophan is required for T lymphocyte effector functions. Its degradation is one of the mechanisms selected by tumors to resist immune destruction. Two enzymes, tryptophan-2,3-dioxygenase and indoleamine 2,3-dioxygenase 1, control tryptophan degradation through the kynurenine pathway. A third protein, indoleamine 2,3-dioxygenase 2, was identified more recently. All three enzymes were reported to be expressed in tumors, and are candidate targets for pharmacological inhibition aimed at restoring effective anti-tumoral immunity. In this review, we compare these three enzymes in terms of structure, activity, regulation, and expression in healthy and cancerous tissues, in order to appreciate their relevance to tumoral immune resistance.

Indoleamine 2, 3-dioxygenases (IDO1 and IDO2) and tryptophan 2, 3-dioxygenase (TDO) are tryptophan catabolic enzymes that catalyze the conversion of tryptophan into kynurenine. The depletion of tryptophan and the increase in kynurenine exert important immunosuppressive functions by activating T regulatory cells and myeloid-derived suppressor cells, suppressing the functions of effector T and natural killer cells, and promoting neovascularization of solid tumors. Targeting IDO1 represents a therapeutic opportunity in cancer immunotherapy beyond checkpoint blockade or adoptive transfer of chimeric antigen receptor T cells. In this review, we discuss the function of the IDO1 pathway in tumor progression and immune surveillance. We highlight recent preclinical and clinical progress in targeting the IDO1 pathway in cancer therapeutics, including peptide vaccines, expression inhibitors, enzymatic inhibitors, and effector inhibitors.

Metabolism of tryptophan (Trp), an essential amino acid, represent a major metabolic pathway that both promotes tumor cell intrinsic malignant properties as well as restricts antitumour immunity, thus emerging as a drug development target for cancer immunotherapy. Three cytosolic enzymes, namely indoleamine 2,3-dioxygenase 1 (IDO1), IDO2 and tryptophan 2,3-dioxygenase (TDO2), catalyzes the first-rate limiting step of the degradation of Trp to kynurenine (Kyn) and modulates immunity toward immunosuppression mainly through the aryl hydrocarbon receptor (AhR) activation in numerous types of cancer. By restoring antitumor immune responses and synergizing with other immunotherapies, the encouraging preclinical data of IDO1 inhibitors has dramatically failed to translate into clinical success when combined with immune checkpoints inhibitors, reigniting the debate of combinatorial approach. In this review, we i) provide comprehensive evidences on immunomodulatory role of the Trp catabolism metabolites that highlight this pathway as relevant target in immuno-oncology, ii)ii) discuss underwhelming results from clinical trials investigating efficacy of IDO1 inhibitors and underlying mechanisms that might have contributed to this failure, and finally, iii) discuss the current state-of-art surrounding alternative approaches of innovative antitumor immunotherapies that target molecules of Trp catabolism as well as challenges and perspectives in the era of immunotherapy.

Tryptophan (Trp), an essential amino acid, is solely acquired through dietary intake. It is vital for protein biosynthesis and acts as a precursor for numerous key bioactive compounds. The Kynurenine Pathway and the Indole Pathway are the main metabolic routes and are extensively involved in the occurrence and progression of diseases in the digestive, nervous, and urinary systems. In the Kynurenine Pathway, enzymes crucial to tryptophan metabolism, indoleamine‐2,3‐dioxygenase 1 (IDO1), IDO2, and Trp‐2,3‐dioxygenase (TDO), trigger tumor immune resistance within the tumor microenvironment and nearby lymph nodes by depleting Trp or by activating the Aromatic Hydrocarbon Receptor (AhR) through its metabolites. Furthermore, IDO1 can influence immune responses via non‐enzymatic pathways. The Kynurenine Pathway exerts its effects on tumor growth through various mechanisms, including NAD+ regulation, angiogenesis promotion, tumor metastasis enhancement, and the inhibition of tumor ferroptosis. In the Indole Pathway, indole and its related metabolites are involved in gastrointestinal homeostasis, tumor immunity, and drug resistance. The gut microbiota related to indole metabolism plays a critical role in determining the effectiveness of tumor treatment strategies and can influence the efficacy of immunochemotherapy. It is worth noting that there are conflicting effects of the Kynurenine Pathway and the Indole Pathway on the same tumor phenotype. For example, different tryptophan metabolites affect the cell cycle differently, and indole metabolism has inconsistent protective effects on tumors in different regions. These differences may hold potential for enhancing therapeutic efficacy.

The Aryl hydrocarbon receptor (AhR) is a xenobiotic and endobiotic receptor, which regulates many cellular processes from contaminant metabolism to immunomodulation. Consequently, it is also involved in pathophysiological pathways and now represents a potential therapeutical target. In this review, we will highlight the ancestral function of the protein together with an illustration of its ligand’s battery, emphasizing the different responses triggered by these high diverse molecules. Among them, several members of the kynurenine pathway (one key process of tryptophan catabolism) are AhR agonists and are subsequently involved in regulatory functions. We will finally display the interplay between Tryptophan (Trp) catabolism and dysregulation in metabolic pathways drawing hypothesis on the involvement of the AhR pathway in these cancer-related processes.

Simple Summary There is clear evidence that inflammation can contribute to the development of cancers, but the underlying mechanisms are not fully understood. This review focuses on metabolites of the amino acid tryptophan, especially kynurenine and related compounds, which are produced in response to inflammation and which have been implicated in cancer progression. Unfortunately, one drug that inhibits the generation of these compounds, epacadostat, has not been very successful. The review explains the actions of each of the relevant tryptophan metabolites and discusses how they interact with other compounds and biochemical pathways known to affect cancer formation. The objective is to demonstrate that the kynurenine pathway could be targeted to affect those interacting pathways indirectly and that those alternative routes could represent a means of modifying tryptophan metabolism indirectly. In either case, the range of possible targets for drugs that inhibit the link between inflammation and cancer would be expanded. Abstract The mechanisms underlying a relationship between inflammation and cancer are unclear, but much emphasis has been placed on the role of tryptophan metabolism to kynurenine and downstream metabolites, as these make a substantial contribution to the regulation of immune tolerance and susceptibility to cancer. The proposed link is supported by the induction of tryptophan metabolism by indoleamine-2,3-dioxygenase (IDO) or tryptophan-2,3-dioxygenase (TDO), in response to injury, infection or stress. This review will summarize the kynurenine pathway and will then focus on the bi-directional interactions with other transduction pathways and cancer-related factors. The kynurenine pathway can interact with and modify activity in many other transduction systems, potentially generating an extended web of effects other than the direct effects of kynurenine and its metabolites. Conversely, the pharmacological targeting of those other systems could greatly enhance the efficacy of changes in the kynurenine pathway. Indeed, manipulating those interacting pathways could affect inflammatory status and tumor development indirectly via the kynurenine pathway, while pharmacological modulation of the kynurenine pathway could indirectly influence anti-cancer protection. While current efforts are progressing to account for the failure of selective IDO1 inhibitors to inhibit tumor growth and to devise means of circumventing the issue, it is clear that there are wider factors involving the relationship between kynurenines and cancer that merit detailed consideration as alternative drug targets.

… AhR signaling activated by the KP metabolites kynurenine … AhR as a suitable therapeutic target for a diverse brain tumor … the efficacy of targeting AhR across various tumor types and …

The current studies associated with tumor biology continue to describe a high correlation between tryptophan (Trp) metabolism and tumor progression. These findings reflect the complex underlying mechanism of tumor development and highlight the need to explore additional drug targets for carcinoma‐associated diseases. In our study, we reported that elevated Trp metabolism was observed in highly malignant glioma tumor tissues from patients. The elevated Trp metabolism in glioma cells were induced by the overexpression of Trp 2,3‐dioxygenase 2 (TDO2), which further contributed to the production of the metabolite kynurenine (Kyn). Subsequently, the Kyn derived from Trp metabolism was able to mediate the activation of the aryl hydrocarbon receptor (AhR) and downstream PI3K/AKT signals, resulting in the strengthening of tumor stemness and growth. Meanwhile, the activation of the AhR could promote the process of epithelial−mesenchymal transition in gliomas through a TGF‐β‐dependent mechanism, leading to enhanced tumor invasion in vitro and in vivo. Inhibition of the AhR using StemRegenin 1 was demonstrated to suppress glioma growth and improve the outcome of traditional chemotherapy in subcutaneous tumor‐bearing mice, representing a promising therapeutic target for clinical glioma treatment.

BACKGROUND Although therapeutic antibodies against immune checkpoints such as PD-1/PD-L1 have achieved unprecedented success in clinical tumor patients, there are still many patients who are ineffective or have limited responses to immune checkpoint blockade (ICB). Discovery of novel strategies for cancer immunotherapy including natural small molecules is needed. METHODS Owing to its extremely low content in Epimedium genus, we firstly constructed a microbial cell factory to enzymatically biosynthesize icariside I, a natural flavonoid monosaccharide from Herbal Epimedium. Using a combination of targeted MS-based metabolomics, flow cytometric analysis, and biological assays, the therapeutic potentials of icariside I were subsequently investigated in vivo and in vitro. RESULTS We find that icariside I markedly downregulates a series of intermediate metabolites such as kynurenine, kynurenic acid and xanthurenic acid and corresponding key enzymes involved in kynurenine-AhR pathway in both tumor cells and tumor-bearing mice. In vivo, oral administration of icariside I downregulates SLC7A8 and PAT4 transporters and AhR, thus inhibiting nuclear PD-1 in CTLs. Moreover, icariside I significantly upregulates CD8 + T cells in both peripheral blood and tumor tissues of tumor-bearing mice. Consequently, interferon-γ (IFN-γ) secreted by CD8 + T cells suppresses tumor growth through activation of JAK1-STAT1 signaling, thus inducing tumor cell apoptosis. CONCLUSIONS These results suggest that icariside I could be an effective small molecule drug for tumor immunotherapy by blocking kynurenine-AhR pathway and tumor immune escape.

Background & Aims Chronic inflammation in colon section is associated with an increased risk of colorectal cancer (CRC). Proinflammatory cytokines were produced in a tumor microenvironment and correlated with poor clinical outcome. Tumor-infiltrating T cells were reported to be greatly involved in the development of colon cancer. In this study, we demonstrated that kynurenine (Kyn), a metabolite catalyzed by indoleamine 2,3-dioxygenase (IDO), was required for IDO-mediated T cell function, and adaptive immunity indeed played a critical role in CRC. Methods Supernatant of colon cancer cells was used to culture activated T cells and mice spleen lymphocytes, and the IDO1-Kyn-aryl hydrocarbon (AhR) receptor axis was determined in vitro. In vivo, an azoxymethane (AOM)/dextran sodium sulfate (DSS)–induced CRC model was established in IDO–/–, Rag1–/–, and wild-type mice, and tumor-associated T lymphocyte infiltration and Kyn/AhR signaling pathway changes were measured in each group. Results Kyn promoted AhR nuclear translocation increased the transcription of Foxp3, a marker of regulatory T cells (Tregs), through improving the interaction between AhR and Foxp3 promoter. Additionally, compared WT mice, IDO–/– mice treated with AOM/DSS exhibited fewer and smaller tumor burdens in the colon, with less Treg and more CD8+ T cells infiltration, while Kyn administration abolished this regulation. Rag1–/– mice were more sensitive to AOM/DSS-induced colitis-associated colon cancer (CRC) compared with the wild-type mice, suggesting that T cell–mediated adaptive immunity indeed played a critical role in CRC. Conclusions We demonstrated that inhibition of IDO diminished Kyn/AhR-mediated Treg differentiation and could be an effective strategy for the prevention and treatment of inflammation-related colon cancer.

Upregulation of the Kynurenine Pathway (KP) in Glioblastoma (GBM) plays an important role in driving its treatment-resistant immunosuppressive microenvironment. Factors driving this exaggerated pathway remain poorly understood. Our aim was to explore the correlation between key KP markers; IDO1, IDO2, TDO2, its primary effector target aryl hydrocarbon receptor (AhR) and a comprehensive set of clinical- and tumour characteristics. Tissue samples from 108 newly diagnosed GBM patients were analyzed for the expression of TDO2, IDO1, IDO2, and AhR using immunohistochemistry and QuPath software. Exploratory analyses were conducted to evaluate correlations between KP marker expression and clinical, radiological, and molecular data. IDO1 expression was primarily correlated with inflammatory blood markers, while TDO2 was correlated with patient age, gender, smoking habit and medication use. In contrast, AhR and IDO2 demonstrated hardly any correlations with clinical or tumour characteristics. Notably, IDO2 exhibited a strong association with AhR expression and tumour cell density, with no observed correlation between AhR and either IDO1 or TDO2. We validated the inflammatory influences on IDO1 expression and found that TDO2 was mostly correlated with medication and patient characteristics. We could not confirm IDO1 and TDO2 as most prominent drivers of AhR activity in the KP. However, we found a strong correlation between IDO2-AhR which may be responsible for the sustained and enhanced immunosuppression within the tumour microenvironment. This could explain recent failures of IDO1 and TDO2 antagonists and might redirect future studies to intervene in the kynurenine-AhR-IDO2 axis.

Tryptophan catabolism by the enzymes indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase 2 (IDO/TDO) promotes immunosuppression across different cancer types. The tryptophan metabolite L-Kynurenine (Kyn) interacts with the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) to drive the generation of Tregs and tolerogenic myeloid cells and PD-1 up-regulation in CD8+ T cells. Here, we show that the AHR pathway is selectively active in IDO/TDO-overexpressing tumors and is associated with resistance to immune checkpoint inhibitors. We demonstrate that IDO-Kyn-AHR-mediated immunosuppression depends on an interplay between Tregs and tumor-associated macrophages, which can be reversed by AHR inhibition. Selective AHR blockade delays progression in IDO/TDO-overexpressing tumors, and its efficacy is improved in combination with PD-1 blockade. Our findings suggest that blocking the AHR pathway in IDO/TDO expressing tumors would overcome the limitation of single IDO or TDO targeting agents and constitutes a personalized approach to immunotherapy, particularly in combination with immune checkpoint inhibitors. The tryptophan metabolite kynurenine is an endogenous ligand of the aryl hydrocarbon receptor (AHR). Here, the authors show that AHR targeting in IDO/TDO-expressing tumours counteracts a regulatory T cell/macrophage suppressive axis and synergizes with immune checkpoint blockade to hinder tumour growth.

Indoleamine 2,3-dioxygenase 1 (IDO1), indoleamine 2,3-dioxygenase 2 (IDO2), and tryptophan 2,3-dioxygenase (TDO) initiate the first step of the kynurenine pathway (KP), leading to the transformation of l -tryptophan (Trp) into l -kynurenine (Kyn) and other downstream metabolites. Kyn is known as an endogenous ligand of the aryl hydrocarbon receptor (AhR). Activation of AhR through TDO-derived Kyn is a novel mechanism to support tumor growth in gliomas. However, the role of IDO1 and IDO2 in this mechanism is still unknown. Herein, by using clinical samples, we found that the expression and activity of IDO1 and/or TDO (IDO1/TDO) rather than IDO2 were positively correlated with the pathologic grades of gliomas. The expression of IDO1/TDO rather than IDO2 was positively correlated with the Ki67 index and overall survival. The expression of IDO1/TDO was positively correlated with the expression of aquaporin 4 (AQP4), implying the potential involvement of IDO1/TDO in glioma cell motility. Mechanistically, we found that IDO1/TDO accounted for the release of Kyn, which activated AhR to promote cell motility via the Kyn–AhR–AQP4 signaling pathway in U87MG glioma cells. RY103, an IDO1/TDO dual inhibitor, could block the IDO1/TDO–Kyn–AhR–AQP4 signaling pathway and exert anti-glioma effects in GL261 orthotopic glioma mice. Together, our results showed that the IDO1/TDO–Kyn–AhR–AQP4 signaling pathway is a new mechanism underlying the malignancy of gliomas, and suggest that both IDO1 and TDO might be valuable therapeutic targets for gliomas.

… that tumor-repopulating cells (TRCs) drive PD-1 upregulation in CD8 + T cells through a transcellular kynurenine (Kyn)-aryl hydrocarbon receptor (AhR) pathway. … and activates AhR and …

Increasing epidemiological and animal experimental data provide substantial support for the role of aryl hydrocarbon receptor (AhR) in mammary tumorigenesis. The effects of AhR have been clearly demonstrated in rodent models of breast carcinogenesis and in several established human breast cancer cell lines following exposure to AhR ligands or AhR overexpression. However, relatively little is known about the role of AhR in human breast cancers. AhR has always been considered to be a regulator of toxic and carcinogenic responses to environmental contaminants such as TCDD (dioxin) and benzo[a]pyrene (BaP). The aim of this study was to identify the type of breast tumors (ERα-positive or ERα-negative) that express AHR and how AhR affects human tumorigenesis. The levels of AHR, AHR nuclear translocator (ARNT) and AHR repressor (AHRR) mRNA expression were analyzed in a cohort of 439 breast tumors, demonstrating a weak association between high AHR expression and age greater than fifty years and ERα-negative status, and HR-/ERBB2 breast cancer subtypes. AHRR mRNA expression was associated with metastasis-free survival, while AHR mRNA expression was not. Immunohistochemistry revealed the presence of AhR protein in both tumor cells (nucleus and/or cytoplasm) and the tumor microenvironment (including endothelial cells and lymphocytes). High AHR expression was correlated with high expression of several genes involved in signaling pathways related to inflammation (IL1B, IL6, TNF, IL8 and CXCR4), metabolism (IDO1 and TDO2 from the kynurenine pathway), invasion (MMP1, MMP2 and PLAU), and IGF signaling (IGF2R, IGF1R and TGFB1). Two well-known ligands for AHR (TCDD and BaP) induced mRNA expression of IL1B and IL6 in an ERα-negative breast tumor cell line. The breast cancer ER status likely influences AhR activity involved in these signaling pathways. The mechanisms involved in AhR activation and target gene expression in breast cancers are also discussed.

Background: The incidence of renal cell carcinoma (RCC) is increasing year by year. It is difficult to have complete treatment so far. Studies have shown that tryptophan metabolite Kynurenine (Kyn) affects cell proliferation, migration, apoptosis, adhesion, and differentiation. Our aim is to explore whether Kyn activates aromatic hydrocarbon receptor (AhR) to mediate RCC metastasis. Methods: We collected RCC tissues and feces from RCC patients. 16S rRNA technology was performed to analyze the gut microbial composition of RCC patients. LC-MS/MS was used to analyze the gut microbial metabolites. The AhR was inhibited and treated with Kyn. Immunofluorescence was used to measure the degree of AhR activation. The migration and invasion ability of 786-O cells was tested by Transwell assay. Flow cytometry and cell cycle assay were utilized to observe the apoptosis and cycle of 786-O cells. CCK-8 assay was used to detect 786-O cells proliferation. qRT-PCR and Western blot were used to detect AhR and EMT-related genes expression level. Results: AhR expression was up-regulated in RCC tissues. RCC gut microbiota was disordered. The proportion of Kyn was increased in RCC. After being treated with Kyn, the migration, invasion, and proliferation ability of 786-O cells were decreased. Furthermore, the expression of EMT-related protein E-cadherin decreased, and the expression of N-cadherin and Vimentin increased. The proportion of 786-O cells in the S phase increased. The apoptosis rate of 786-O cells was inhibited. Conclusion: The tryptophan metabolite Kyn could activate AhR. Kyn could promote 786-O cells migration and invasion. Gut microbiota could activate AhR through its tryptophan metabolite Kyn to mediate RCC metastasis.

BACKGROUND L-kynurenine, derivate of L-tryptophan, is synthetized by indoleamine 2,3-dioxygenase (IDO). The effects of L-kynurenine depend on its binding to an aryl hydrocarbon receptor (AhR). OBJECTIVE The aim of this study was to investigate the changes within the apoptotic pathway in PANC-1 cells subjected to L-kynurenine or L-tryptophan considering the production of anti-apoptotic proteins from the IAPs and Bcl-2 family, as well as the regulation of NF-κB signaling. METHOD The investigated substances were added alone or in combination with the AhR inhibitor (CH223191) to cultures of PANC-1 cells. Cytoplasmic and nuclear proteins were analyzed by immunoblotting and cells were incubated with the investigated substances to determine cytotoxicity and proliferative effects. RESULTS Incubation of PANC-1 cells with L-kynurenine or L-tryptophan resulted in the increase of anti-apoptotic cIAP-1, cIAP-2, XIAP and Bcl-2 expression and a decrease of pro-apoptotic Bax. These changes were accompanied by the reduction of active caspases -9, -3 and PARP-1. The treatment leads to translocation and enhanced production of nuclear NF-κB p50 and Bcl-3. Incubation of the cells with AhR blocker either alone or together with L-kynurenine or L-tryptophan resulted in the opposite effect, leading to the downregulation of IAPs and Bcl-2, upregulation of Bax and caspases expression. CONCLUSION 1) L-kynurenine and its precursor promote anti-apoptotic effects through the modulation of IDO-dependent pathway and regulation of IAPs, Bcl-2 and NF-κB family members in pancreatic carcinoma cells 2) inhibition of AhR by CH223191 exerts an apoptosis-promoting effect, and this observation might suggest the potential use of this compound in pancreatic cancer therapy.

Neuroblastoma (NB) is the most common malignant disease of infancy, and amplification of the MYCN oncogene is closely associated with poor prognosis. Recently, expression of MYCN was shown to be inversely correlated with aryl hydrocarbon receptor (AHR) expression in NB, and overexpression of AHR downregulated MYCN expression, promoting cell differentiation. Therefore, we further investigated the potential of AHR to serve as a prognostic indicator or a therapeutic target in NB. First, the clinical significance of AHR in NB was examined. Positive AHR immunostaining strongly correlated with differentiated histology of NB and predicted better survival for patients. The mouse xenograft model showed that overexpression of AHR significantly suppressed NB tumor growth. In addition, activation of AHR by the endogenous ligand kynurenine (Kyn) inhibited cell proliferation and promoted cell differentiation in vitro and in vivo. Kyn treatment also upregulated the expression of KISS1, a tumor metastasis suppressor, and attenuated metastasis in the xenograft model. Lastly, analysis of KISS1 levels in NB patient tumors using the R2: Genomics Analysis and Visualization Platform revealed that KISS1 expression positively correlated with AHR, and high KISS1 expression predicted better survival for patients. In conclusion, our results indicate that AHR is a novel prognostic biomarker for NB, and that overexpression or activation of AHR offers a new therapeutic possibility for NB patients.

Simple Summary The kynurenine pathway has two main physiological roles: (i) it protects specific organs such as the eyes and placenta from strong immune reactions and (ii) it additionally generate in the liver and kidney a metabolite essential to all cells of human body. Abnormal activation of this pathway is recurrently observed in numerous cancer types. Its two functions are hijacked to promote tumor growth and cancer cell dissemination through multiple mechanisms. Clinical assays including administration of inhibitors of this pathway have not yet been successful. The complex regulation of this pathway is likely the reason behind this failure. In this review, we try to give an overview of the current knowledge about this pathway, to point out the next challenges, and to propose alternative therapeutic routes. Abstract The kynurenine pathway has been highlighted as a gatekeeper of immune-privileged sites through its ability to generate from tryptophan a set of immunosuppressive metabolic intermediates. It additionally constitutes an important source of cellular NAD+ for the organism. Hijacking of its immunosuppressive functions, as recurrently observed in multiple cancers, facilitates immune evasion and promotes tumor development. Based on these observations, researchers have focused on characterizing indoleamine 2,3-dioxygenase (IDO1), the main enzyme catalyzing the first and limiting step of the pathway, and on developing therapies targeting it. Unfortunately, clinical trials studying IDO1 inhibitors have thus far not met expectations, highlighting the need to unravel this complex signaling pathway further. Recent advances demonstrate that these metabolites additionally promote tumor growth, metastatic dissemination and chemoresistance by a combination of paracrine and autocrine effects. Production of NAD+ also contributes to cancer progression by providing cancer cells with enhanced plasticity, invasive properties and chemoresistance. A comprehensive survey of this complexity is challenging but necessary to achieve medical success.

Primary brain tumors, both malignant and benign, are diagnosed in adults at an incidence rate of approximately 23 people per 100 thousand. The role of AhR in carcinogenesis has been a subject of debate, given that this protein may act as either an oncogenic protein or a tumor suppressor in different cell types and contexts. Lately, there is growing evidence that aryl hydrocarbon receptor (AhR) plays an important part in the development of brain tumors. The role of AhR in brain tumors is complicated, depending on the type of tumor, on ligands that activate AhR, and other features of the pathological process. In this review, we summarize current knowledge about AhR in relation to brain tumors and provide an overview of AhR’s potential as a therapeutic target.

Colorectal cancer (CRC) is one of the most malignant cancers resulting from abnormal metabolism alterations. As one of the essential amino acids, tryptophan has a variety of physiological functions, closely related to regulation of immune system, central nervous system, gastrointestinal nervous system and intestinal microflora. Colorectal cancer, a type of high-grade malignancy disease, stems from a variety of factors and often accompanies inflammatory reactions, dysbacteriosis, and metabolic disorders. Colorectal cancer accompanies inflammation and imbalance of intestinal microbiota and affects tryptophan metabolism. It is known that metabolites, rate-limiting enzymes, and ARH in tryptophan metabolism are associated with the development of CRC. Specifically, IDO1 may be a potential therapeutic target in colorectal cancer treatment. Furthermore, the reduction of tryptophan amount is proportional to the poor quality of life for colorectal cancer patients. This paper aims to discuss the role of tryptophan metabolism in a normal organism and investigate the relationship between this amino acid and colorectal cancer. This study is expected to provide theoretical support for research related to targeted therapy for colorectal cancer. Furthermore, strategies that modify tryptophan metabolism, effectively inhibiting tumor progression, may be more effective for CRC treatment.

The essential amino acid L-tryptophan (Trp) undergoes extensive metabolism along several pathways, resulting in production of many biologically active metabolites which exert profound effects on physiological processes. The disturbance in Trp metabolism and disposition in many disease states provides a basis for exploring multiple targets for pharmaco-therapeutic interventions. In particular, the kynurenine pathway of Trp degradation is currently at the forefront of immunological research and immunotherapy. In this review, I shall consider mammalian Trp metabolism in health and disease and outline the intervention targets. It is hoped that this account will provide a stimulus for pharmacologists and others to conduct further studies in this rich area of biomedical research and therapeutics.

Cancer cells exhibit distinct metabolic activities and nutritional dependencies compared to normal cells. Thus, characterization of nutrient demands by individual tumor types may identify specific vulnerabilities that can be manipulated to target the destruction of cancer cells. We find that MYC-driven liver tumors rely on augmented tryptophan (Trp) uptake, yet Trp utilization to generate metabolites in the kynurenine (Kyn) pathway is reduced. Depriving MYC-driven tumors of Trp through a No-Trp diet not only prevents tumor growth but also restores the transcriptional profile of normal liver cells. Despite Trp starvation, protein synthesis remains unhindered in liver cancer cells. We define a crucial role for the Trp-derived metabolite indole 3-pyruvate (I3P) in liver tumor growth. I3P supplementation effectively restores the growth of liver cancer cells starved of Trp. These findings suggest that I3P is a potential therapeutic target in MYC-driven cancers. Developing methods to target this metabolite represents a potential avenue for liver cancer treatment. Amino acids availability is normally a limitation for protein synthesis and can determine cancer progression and therapy response. Here, the authors show that MYC-associated cancer has a dependency on tryptophan not because of translation regulation, but Indole 3-Pyruvate synthesis.

In this study, Venkateswaran et al. investigated how the proto-oncogene MYC regulates the metabolism of amino acids other than glutamine in cancer. They found that MYC increased intracellular levels of tryptophan and tryptophan metabolites in the kynurenine pathway and that blocking the kynurenine pathway caused preferential death of established colon cancer cells and transformed colonic organoids.

Tumor cells exhibit enhanced metabolism of nutrients to satisfy the demand of sustained proliferation in vivo. Seminal reports have presented evidence that tryptophan (Trp) metabolic reprogramming induced by aberrant indoleamine 2,3-dioxygenases could promote tumor development in several cancer types. However, the underlying mechanism of Trp metabolism associated tumor progression is not fully understood. Prostatic cell lines LNCaP and VCaP were purchased from the Cell Bank of the Chinese Academy of Sciences (China). Human prostatic tumor tissue samples were obtained from the Tongji Hospital. Female NOD-SCID mice (6 ~ 8 weeks) were purchased from Huafukang Co. (China) and raised in SPF room. Commercial kits and instruments were used for cell apoptosis analysis, real-time PCR, western blotting, ELISA analysis and other experiments. Comparing the tumor tissues from prostatic cancer patients, we found elevated expression of tryptophan 2, 3-dioxygenase 2 (TDO2), and elevated Trp metabolism in chemo-resistant tumor tissues. In vitro, overexpression of TDO2 significantly promoted the Trp metabolism in prostatic cancer cell lines LNCaP and VCap, resulting in the multidrug resistance development. Mechanistically, we demonstrated that Trp metabolite kynurenine (Kyn) promoted the upregulation and nuclear translocation of transcription factor aryl hydrocarbon receptor (AhR). Subsequently, AhR collaborated with NF-κB to facilitate the activation of c-Myc. In turn, c-Myc promoted the up-regulation of ATP-binding cassette (ABC) transporters and Trp transporters, thereby contributing to chemoresistance and strengthened Trp metabolism in prostatic cancer. Interrupt of Trp/TDO2/Kyn/AhR/c-Myc loop with c-Myc inhibitor Mycro-3 efficiently suppressed the chemoresistance and improved the outcome of chemotherapy, which described a new strategy in clinical prostatic cancer treatment. Our study demonstrates that elevated TOD2 expression promoted Trp metabolism and metabolite Kyn production, thus resulting in the activation of AhR/c-Myc/ABC-SLC transporters signaling pathway. Interrupt of Trp metabolism/c-Myc loop efficiently suppressed the drugs resistance induced by TDO2, which represented potential target to improve the outcome in drug-resistant prostatic cancer treatment.

Hematological malignancies exhibit distinct patterns of amino acid metabolic reprogramming, which support uncontrolled proliferation, immune escape, and therapy resistance. Rather than merely fueling biosynthesis, amino acid metabolism intricately modulates tumor progression and therapeutic responses through interactions with signaling pathways such as mTOR, β-catenin/c-Myc, and NF-κB. This review emphasizes the rewired utilization of key amino acids—including glutamine, arginine, leucine, tryptophan, and phenylalanine—across leukemia, lymphoma, and multiple myeloma, and discusses how these changes orchestrate immune suppression and redox imbalance. Emerging studies reveal that metabolic vulnerabilities can be therapeutically exploited via enzyme depletion, transport inhibition, or combination regimens with immunotherapies and mTOR inhibitors. Moreover, amino acid-driven drug resistance mechanisms, particularly involving stromal support and transcriptional reprogramming, pose both challenges and opportunities for next-generation treatment design. By decoding the complex metabolic-immune-tumor network, we highlight strategic interventions that leverage amino acid metabolism as a therapeutic axis in hematological cancers.

… Given that PA mainly affected proliferation and metabolic activity, we hypothesized that c-Myc might constitute a molecular target of PA-mediated suppression [20]. Activity of c-Myc is …

… cancer and the current results obtained with IDO inhibition, both in animal models and in phase 1 and 2 … Preliminary results with IDO inhibitors, usually combined with other anti-cancer …

Tumors are composed of abnormally transformed cell types and tissues that differ from normal tissues in their genetic and epigenetic makeup, metabolism, and immunology. Molecular compounds that modulate the immune response against neoplasms offer promising new strategies to combat cancer. Inhibitors targeting the indoleamine-2,3-dioxygenase 1 enzyme (IDO1) represent one of the most potent therapeutic opportunities to inhibit tumor growth. Herein, we assess the biochemical role of IDO1 in tumor metabolism and immune surveillance, and review current diagnostic and therapeutic approaches that are intended to increase the effectiveness of immunotherapies against highly aggressive and difficult-to-treat IDO-expressing cancers.

… Indoleamine-2,3-dioxygenase (IDO) is an immunosuppressive enzyme capable of inhibiting a destructive maternal T cell response against allogeneic fetuses. Expression of IDO is …

Tumor cells escape the immune surveillance system of the host through a process called immune tolerance. Immunotherapy targets molecules that serve as checks and balances in the regulation of immune response. Indoleamine-2,3-dioxygenase (IDO) is an intracellular enzyme, which through the process of tryptophan depletion exerts an immunosuppressive effect, facilitating immune escape of tumors. This review summarizes our current knowledge on IDO expression in malignancies, the IDO inhibitors that are currently available and those under clinical development.

… Prevention of spontaneous tumor development in a ret transgenic mouse model by ret peptide vaccination with indoleamine 2,3dioxygenase inhibitor 1-methyl tryptophan. …

… of reports describing inhibition studies of indoleamine 2,3-dioxygenase (IDO, EC 1.13.11.17)… 2,3-dioxygenase (TDO2, EC 1.13.11.11). Both competitive and noncompetitive inhibitors of …

&NA; Immunotherapy through immune checkpoint blockers (ICBs) is quickly transforming cancer treatment by improving patients' outcomes. However, innate and acquired resistance to ICBs remain a major challenge in clinical settings. Indoleamine 2,3‐dioxygenases (IDOs) are enzymes involved in tryptophan catabolism with a central immunosuppressive function within the tumor microenvironment. IDOs are over‐expressed in cancer patients and have increasingly been associated with worse outcomes and a poor prognosis. Preclinical data have shown that combining IDO and checkpoint inhibition might be a valuable strategy to improve the efficacy of immunotherapy. Currently, several IDO inhibitors have been evaluated in clinical trials, showing favorable pharmacokinetic profiles and promising efficacy. This review describes the mechanisms involved in IDO‐mediated immune suppression and its role in cancer immune escape, focusing on the potential clinical application of IDO inhibitors as an immunotherapy strategy for cancer treatment.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme enzyme that catalyzes the oxidation of L -tryptophan. Functionally, IDO1 has played a pivotal role in cancer immune escape via catalyzing the initial step of the kynurenine pathway, and overexpression of IDO1 is also associated with poor prognosis in various cancers. Currently, several small-molecule candidates and peptide vaccines are currently being assessed in clinical trials. Furthermore, the “proteolysis targeting chimera” (PROTAC) technology has also been successfully used in the development of IDO1 degraders, providing novel therapeutics for cancers. Herein, we review the biological functions of IDO1, structural biology and also extensively summarize medicinal chemistry strategies for the development of IDO1 inhibitors in clinical trials. The emerging PROTAC-based IDO1 degraders are also highlighted. This review may provide a comprehensive and updated overview on IDO1 inhibitors and their therapeutic potentials.

… can be heightened safely by a clinical lead inhibitor of the IDO pathway that relieves IDO-… in cancer, we provide a conceptual foundation for the clinical development of IDO inhibitors as …

… The molecular mechanisms of tumor-induced tolerance are … indoleamine 2,3-dioxygenase (IDO; EC 1.13.11.52) plays an important role in immune escape of cancer [Citation1,Citation2]. …

The activity and expression of indoleamine 2,3-dioxygenase together with L-tryptophan transport has been examined in cultured human breast cancer cells. MDA-MB-231 but not MCF-7 cells expressed mRNA for indoleamine 2,3-dioxygenase. Kynurenine production by MDA-MB-231 cells, which was taken as a measure of enzyme activity, was markedly stimulated by interferon-gamma (1000 units/ml). Accordingly, L-tryptophan utilization by MDA-MB-231 cells was enhanced by interferon-gamma. 1-Methyl-DL-tryptophan (1 mM) inhibited interferon-gamma induced kynurenine production by MBA-MB-231 cells. Kynurenine production by MCF-7 cells remained at basal levels when cultured in the presence of interferon-gamma. L-Tryptophan transport into MDA-MB-231 cells was via a Na(+)-independent, BCH-sensitive pathway. It appears that system L (LAT1/CD98) may be the only pathway for l-tryptophan transport into these cells. 1-Methyl-D,L-tryptophan trans-stimulated l-tryptophan efflux from MDA-MB-231 cells and thus appears to be a transported substrate of system L. The results suggest that system L plays an important role in providing indoleamine-2,3-dioxygenase with its main substrate, L-tryptophan, and suggest a mechanism by which estrogen receptor-negative breast cancer cells may evade the attention of the immune system.

Purpose Breast cancer has become a major public health threat in the current society. Anthracycline doxorubicin (DOX) is a widely used drug in breast cancer chemotherapy. We aimed to investigate the immunogenic death of breast tumor cells caused by DOX, and detect the effects of combination of DOX and a small molecule inhibitor in tumor engrafted mouse model. Methods We used 4T1 breast cancer cells to examine the anthracycline DOX-mediated immunogenic death of breast tumor cells by assessing the calreticulin exposure and adenosine triphosphate and high mobility group box 1 release. Using 4T1 tumor cell-engrafted mouse model, we also detected the expression of indoleamine 2,3-dioxygenase (IDO) in tumor tissues after DOX treatment and further explored whether the specific small molecule IDO1 inhibitor NLG919 combined with DOX, can exhibit better therapeutic effects on breast cancer. Results DOX induced immunogenic cell death of murine breast cancer cells 4T1 as well as the upregulation of IDO1. We also found that treatment with NLG919 enhanced kynurenine inhibition in a dose-dependent manner. IDO1 inhibition reversed CD8+ T cell suppression mediated by IDO-expressing 4T1 murine breast cancer cells. Compared to the single agent or control, combination of DOX and NLG919 significantly inhibited the tumor growth, indicating that the 2 drugs exhibit synergistic effect. The combination therapy also increased the expression of transforming growth factor-β, while lowering the expressions of interleukin-12p70 and interferon-γ. Conclusion Compared to single agent therapy, combination of NLG919 with DOX demonstrated better therapeutic effects in 4T1 murine breast tumor model. IDO inhibition by NLG919 enhanced the therapeutic efficacy of DOX in breast cancer, achieving synergistic effect.

Expression of indoleamine 2,3-dioxygenase (IDO) in primary breast cancer increases tumor growth and metastasis. However, the clinical significance of stromal IDO and the regulation of stromal IDO are unclear. Metabolomics and enzyme-linked immunosorbent assay (ELISA) were used to study the effect of cyclooxygenase-2 (COX-2)-overexpressing breast cancer cells on IDO expression in co-cultured human breast fibroblasts. Biochemical inhibitors and short-hairpin RNA (shRNA) were used to clarify how prostaglandin E2 (PGE2) upregulates IDO expression. Associations of stromal IDO with clinicopathologic parameters were tested in tumor specimens. An orthotopic animal model was used to examine the effect of COX-2 and IDO inhibitors on tumor growth. Kynurenine, the metabolite generated by IDO, increases in the supernatant of fibroblasts co-cultured with COX-2-overexpressing breast cancer cells. PGE2 released by cancer cells upregulates IDO expression in fibroblasts through an EP4/signal transducer and activator of transcription 3 (STAT3)-dependent pathway. Conversely, fibroblast-secreted kynurenine promotes the formation of the E-cadherin/Aryl hydrocarbon receptor (AhR)/S-phase kinase-associated protein 2 (Skp2) complex, resulting in degradation of E-cadherin to increase breast cancer invasiveness. The enhancement of motility of breast cancer cells induced by co-culture with fibroblasts is suppressed by the IDO inhibitor 1-methyl-tryptophan. Pathological analysis demonstrates that upregulation of stromal IDO is a poor prognosis factor and is associated with of COX-2 overexpression. Co-expression of cancer COX-2 and stromal IDO predicts a worse disease-free and metastasis-free survival. Finally, COX-2 and IDO inhibitors inhibit tumor growth in vivo. Integration of metabolomics and molecular and pathological approaches reveals the interplay between cancer and stroma via COX-2, and IDO promotes tumor progression and predicts poor patient survival.

Significant progress has been made in cancer immunotherapy with checkpoint inhibitors targeting programmed cell death protein 1 (PD-1)–programmed death-ligand 1 signaling pathways. Tumors from patients showing sustained treatment response predominately demonstrate a T cell–inflamed tumor microenvironment prior to, or early on, treatment. Not all tumors with this phenotype respond, however, and one mediator of immunosuppression in T cell–inflamed tumors is the tryptophan–kynurenine–aryl hydrocarbon receptor (Trp–Kyn–AhR) pathway. Multiple mechanisms of immunosuppression may be mediated by this pathway including depletion of tryptophan, direct immunosuppression of Kyn, and activity of Kyn-bound AhR. Indoleamine 2,3-dioxygenase 1 (IDO1), a principle enzyme in Trp catabolism, is the target of small-molecule inhibitors in clinical development in combination with PD-1 checkpoint inhibitors. Despite promising results in early-phase clinical trials in a range of tumor types, a phase III study of the IDO1-selective inhibitor epacadostat in combination with pembrolizumab showed no difference between the epacadostat-treated group versus placebo in patients with metastatic melanoma. This has led to a diminution of interest in IDO1 inhibitors; however, other approaches to inhibit this pathway continue to be considered. Novel Trp–Kyn–AhR pathway inhibitors, such as Kyn-degrading enzymes, direct AhR antagonists, and tryptophan mimetics are advancing in early-stage or preclinical development. Despite uncertainty surrounding IDO1 inhibition, ample preclinical evidence supports continued development of Trp–Kyn–AhR pathway inhibitors to augment immune-checkpoint and other cancer therapies.

Pancreatic ductal adenocarcinoma (PDAC) is the most common exocrine tumor of the pancreas characterized by late diagnosis, adverse overall 5-year survival, a higher propensity for metastatic disease, and lack of efficacy of systemic therapy options. These adverse outcomes can be partly attributed to complex tumor microenvironment (TME). Over the past decade, immunotherapy has revolutionized the management of certain cancers; thus far, the immunologically ‘non-inflamed’ tumor microenvironment in PDACs has proven to be challenging. Indolamine 2,3-dioxygenase 1 (IDO1) is the rate-limiting enzyme in the catabolic pathway of L-Tryptophan, an essential amino acid, that gives rise to the immunosuppressive metabolite Kynurenine. IDO1, Indolamine 2,3-dioxygenase 2 (IDO2), and Tryptophan 2,3-dioxygenase (TDO) are the key enzymes in the tryptophan catabolic pathway but we focus on the role of the predominant enzyme form IDO1 in this review. Nicotinamide phosphoribosyl transferase (iNAMPT) regulates the intracellular concentration of NAD and is upregulated in the tumor. In light of the potential role of IDO1 as a driver of hostile TME in PDAC and NAD+ as a key coenzyme in anti-tumor immune response, this review urges focus on extensive research and initiation of clinical trials using IDO1 and NAMPT inhibitors in pancreatic cancer in the future.

Head and neck squamous cell carcinoma (HNSCC) develops within a chronically inflamed tumor microenvironment (TME) where metabolic reprogramming and immune suppression tightly co-evolve. A prominent example is the tryptophan–kynurenine (Trp–Kyn) pathway, initiated by indoleamine 2,3-dioxygenase 1/2 (IDO1/IDO2) and tryptophan 2,3-dioxygenase (TDO2), which converts tryptophan into kynurenine and downstream metabolites that engage stress-response programs and aryl hydrocarbon receptor (AhR) signaling. In HNSCC, Trp–Kyn enzymes are inducible by interferons and oncogenic cues and are distributed across malignant cells as well as cancer-associated fibroblasts, endothelial cells and tumor-associated myeloid populations, generating spatially restricted “Trp-low/Kyn-high” immunometabolic niches. Within these niches, tryptophan starvation and kynurenine-driven signaling converge to suppress effector T-cell expansion, promote regulatory T-cell programs, undermine dendritic-cell priming and reinforce tolerogenic myeloid states, collectively fostering T-cell exhaustion and reduced sensitivity to PD-1/PD-L1 blockade. Emerging bulk, single-cell and spatial multi-omics studies support the idea that pathway activity is compartmentalized rather than uniform, providing a mechanistic rationale for the limited performance of first-generation IDO1 inhibitor strategies in unselected clinical settings. This mini-review synthesizes current evidence on Trp–Kyn microdomains in the HNSCC TME and discusses therapeutic opportunities that move beyond single-enzyme inhibition, including dual IDO1/TDO2 targeting, AhR antagonism and biomarker-guided combination regimens to restore antitumor immunity.

The term “immune privilege” was originally coined to describe the suppression of inflammatory responses within organs protected by anatomic barriers, ie, the eyes, brain, placenta, and testes. However, cellular and metabolic processes, which orchestrate immune responses, also control inflammation within these sites. Our current understanding of tolerogenic mechanisms has extended the definition of immune privilege to include hair follicles, the colon, and cancer. By catabolizing tryptophan, cells expressing the enzyme indoleamine-2,3-dioxygenase produce kynurenine metabolites, which orchestrate local and systemic responses to control inflammation, thus maintaining immune privilege. This review highlights the double-edged role played by the kynurenine pathway (KP), which establishes and maintains immune-privileged sites while contributing to cancer immune escape. The identification of the underlying molecular drivers of the KP in immune-privileged sites and in cancer is essential for the development of novel therapies to treat autoimmunity and cancer and to improve transplantation outcomes.

Evading recognition of immune cells is a well-known strategy of tumors used for their survival. One of the immune evasion mechanisms is the synthesis of kynurenine (KYN), a metabolite of tryptophan, which suppresses the effector T cells. Therefore, lowering the KYN concentration can be an efficient antitumor therapy by restoring the activity of immune cells. Recently, kynureninase (KYNase), which is an enzyme transforming KYN into anthranilate, was demonstrated to show the potential to decrease KYN concentration and inhibit tumor growth. However, due to the limited bioavailability and instability of proteins in vivo, it has been challenging to maintain the KYNase concentration sufficiently high in the tumor microenvironment (TME). Here, we developed a nanoparticle system loaded with KYNase, which formed a Biodegradable and Implantable Nanoparticle Depot named 'BIND' following subcutaneous injection. The BIND sustainably supplied KYNase around the TME while located around the tumor, until it eventually degraded and disappeared. As a result, the BIND system enhanced the proliferation and cytokine production of effector T cells in the TME, followed by tumor growth inhibition and increased mean survival. Finally, we showed that the BIND carrying KYNase significantly synergized with PD-1 blockade in three mouse models of colon cancer, breast cancer, and melanoma.

Immune checkpoint inhibitors (ICIs) have changed therapeutic algorithms in several malignancies, although intrinsic and secondary resistance is still an issue. In this context, the dysregulation of immuno-metabolism plays a leading role both in the tumor microenvironment (TME) and at the host level. In this review, we summarize the most important immune-metabolic factors and how they could be exploited therapeutically. At the cellular level, an increased concentration of extracellular adenosine as well as the depletion of tryptophan and uncontrolled activation of the PI3K/AKT pathway induces an immune-tolerant TME, reducing the response to ICIs. Moreover, aberrant angiogenesis induces a hypoxic environment by recruiting VEGF, Treg cells and immune-suppressive tumor associated macrophages (TAMs). On the other hand, factors such as gender and body mass index seem to affect the response to ICIs, while the microbiome composition (and its alterations) modulates both the response and the development of immune-related adverse events. Exploiting these complex mechanisms is the next goal in immunotherapy. The most successful strategy to date has been the combination of antiangiogenic drugs and ICIs, which prolonged the survival of patients with non-small-cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC), while results from tryptophan pathway inhibition studies are inconclusive. New exciting strategies include targeting the adenosine pathway, TAMs and the microbiota with fecal microbiome transplantation.

Immunotherapy is a potential strategy to suppress the postoperative recurrence and metastasis of triple-negative breast cancer (TNBC). However, the excessive accumulation of kynurenine (Kyn) leads to immunosuppressive tumor microenvironment (TME) and impedes immunotherapeutic efficacy. Herein, a two-pronged approach through "Kynurenine Starvation Therapy" is proposed based on the in-situ hydrogel implantation for postsurgical treatment of TNBC. The hydrogel is constructed via Schiff base reaction between oxidized dextran (ODEX) and 8-arm poly(ethylene glycol) amine (8-arm PEG-NH2), which exhibits excellent biocompatibility and gradual biodegradability. The indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor NLG919 and kynureninase (KYNase) are noncovalently loaded into the hydrogel to prepare NLG919 + KYNase@Gel. The obtained hydrogel can sustainably release NLG919 and KYNase to synergistically deplete Kyn, thereby reversing immunosuppression to enhance the antitumor immunity within TME through "Kynurenine Starvation Therapy". Moreover, a single implantation of NLG919 + KYNase@Gel not only effectively inhibits the postoperative recurrence and metastasis in 4 T1 tumor-bearing mice, but also restrains the growth in an orthotopic TNBC mouse model. These findings highlight an innovative strategy to reinforce the antitumor immune response for the treatment of postsurgical TNBC.

The pivotal role of metabolic reprogramming in cancer-related drug resistance, through the tryptophan-catabolized kynurenine pathway (KP), has been particularly underscored in recent research. This pathway, driven by indoleamine 2,3-dioxygenase 1 (IDO1), facilitates immune evasion and promotes tumor progression by fostering an immunosuppressive environment. In Phase III investigation of the combination of IDO1 inhibition with immune checkpoint inhibitors (ICIs), the combination therapy was not efficacious. In this review, we revisit current advances, explore future directions, and emphasize the importance of dual inhibition of the KP rate-limiting enzymes IDO1 and tryptophan 2,3-dioxygenase-2 (TDO2) in appropriate patient populations. We propose that dual inhibition may maximize the therapeutic potential of KP inhibition. Additionally, we delve into the complex cellular interactions in cancer and metabolic dependencies within the tumor microenvironment (TME). Insights from preclinical studies, recent clinical trials, and promising therapeutic combinations will be discussed to elucidate and promote a clear path forward for the direction of KP research into cancer-related outcomes.

Programmed death-1 (PD-1) acts as a T cell checkpoint and is important in controlling T cell exhaustion. Blocking the intercommunication across PD-1 and PD-L1 is promising for advanced lung cancer treatment. However, the response rate requires being strengthened. This study aimed to determine whether the combination treatment of Qingfei mixture (QFM) and PD-1 inhibitor could improve the sensitivity of monoclonal antibody by regulating STAT1/IDO1-mediated tryptophan (Trp)-kynurenine (Kyn) pathway. The in vivo imaging system, immunofluorescence, hematoxylin-eosin staining, TUNEL, flow cytometry, HPLC, and ELISA were used to estimate the anti-tumor effects in LLC-luc tumor-bearing C57BL/6 mice treated with QFM, PD-1 inhibitor, 2-NP (enhancer of STAT1 transcription), and FICZ (AhR agonist) alone or in combination. IFN-γ-mediated A549 and LLC cells were treated with QFM-containing serum and fludarabine (FLU, STAT1 inhibitor), and cell viability, apoptosis, and Kyn content were then evaluated using CCK-8 assays, flow cytometry, and HPLC assays, respectively. Additionally, the expressions of STAT1, IDO1, AhR, NFATc1, TRIP12, PD-1, and PD-L1 were measured in vivo and in vitro. We found QFM increased the anti-cancer actions of PD-1 inhibitors by increasing the CD8+IFNγ+ T cells infiltration and decreasing the ratio of Kyn/Trp. Besides, QFM-containing serum suppressed the proliferation and promoted apoptosis in A549 and LLC cells, meanwhile, FLU boosted the effects of QFM-containing serum. Moreover, the suppression of tumor growth in the combination therapy was attenuated in the mice receiving 2-NP or FICZ. The occurrence of the above results was accompanied by a decrease in STAT1, IDO1, AhR, PD-1, and PD-L1 expressions. Collectively, the findings suggested that QFM may increase the influences of PD-1 inhibitors at least partially by blocking the STAT1/IDO1-mediated tryptophan-kynurenine pathway in lung cancer.

ABSTRACT Accumulated oncometabolites in the tumor microenvironment (TME) suppresses the metabolism, expansion, and function of T cells. Immunosuppressive TME also impeded Chimeric Antigen Receptor (CAR)-T cells mediated cytotoxicity since CAR-T cells had to adapt the in vivo metabolic characteristics with high levels of oncometabolites. We screened oncometabolites for the inhibition of glucose uptake in CD8 + T cells and found Kynurenine (Kyn) showed the strongest inhibiting effect on glucose uptake. In vitro experiments showed that 120 μM Kyn treatment in CD8 + T cells resulted in inhibiting the expansion of CD8 + T cells, decreasing the production of granzyme B and interferon-γ. CAR-T cells mediated cytotoxicity was also impaired by the high Kyn treatment from killing assay. We then explored the anti-tumor effect of Kynureninase (KYNU) modified CAR-T cells through catabolism o oncometabolites Kyn. KYNU over-expression (OE) CAR-T cells showed a superior killing effect against cancer cells even in the immunosuppressive TME with high Kyn levels. In vivo experiments confirmed KYNU-OE CAR-T cells showed an excellent anti-tumor effect in a TME with high Kyn levels since it improved the survival of mice bearing NALM6 cancer cells and NALM6-IDO1 cancer cells. The KYNU-modified CAR-T cells displayed distinct phenotypes related to the expansion, function, and memory differentiation status of CAR-T cells. This study explores an immunotherapy strategy for patients with alterations in Kyn metabolism. KYNU-OE CAR-T cells take advantage of Kyn catabolism to improve anti-tumor activity in the metabolic immunosuppressive TME with high Kyn.

Background Natural killer (NK) cells play a major role in body’s fighting against various types of cancers. Their infiltration in the tumor microenvironment (TME) of gastric cancer (GC) are significantly decreased, which has been reported as a robust prognostic marker. However, the causes leading to NK cells loss in GC TME remains poorly understood. Methods We constructed a non-contact co-culturing system and humanized xenograft tumor mice model to detect the influence of GC microenvironment on NK-92 or primary human NK cells viability by flow cytometry. Then through using the specific inhibitors for different types of cell death and examining the surrogate markers, we confirmed ferroptosis in NK cells. Inspired by the accidental discoveries, we constructed a NK-92 cell strain with high expression of GPX4 and treated the humanized xenograft tumor mice model with the NK-92 cells. Results We found L-KYN, mainly generated through indoleamine 2, 3-dioxygenase (IDO) from GC cells, impaired NK cells viability in TME. Further analysis revealed L-KYN induced ferroptosis in NK cells via an AHR-independent way. Moreover, we found NK cells with higher GPX4 expression showed resistance to L-KYN induced ferroptosis. Based on this, we generated GPX4 over-expressed NK-92 cells, and found these cells showed therapeutic potential towards GC. Conclusions Our study revealed a novel mechanism to explain the decline of NK cell number in GC TME. Notably, we also developed a potential immunotherapy strategy, which might be beneficial in clinical treatment in the future.

Glioblastoma (GBM) is a universally fatal cancer for which the standard of care has remained largely unchanged for the last 20 years. Recent work has demonstrated that most therapeutic trials for GBM fail due to complex mechanisms of immunosuppression mediated by both the innate and adaptive immune systems. Various metabolic alterations in the tumor microenvironment help maintain this local and systemic immunosuppression, of which the axis of hypoxia-driven tryptophan degradation has garnered substantial attention over the last decade. This paper synthesizes a much-needed elucidation of the immunometabolic reshaping of glioma, myeloid, endothelial, and lymphoid cell lineages induced by hypoxia. The current paper critically evaluates the role of IDO1/TDO2-mediated breakdown of tryptophan and the consequent accumulation of kynurenine, a metabolite that triggers GCN2- and AHR-mediated CD8+ T-cell exhaustion and supports regulatory T-cell differentiation and expansion. Furthermore, we propose a synthesis of mechanistic evidence that establishes a role for the Trp-GCN2-ATF4-VEGFA axis in hypoxia-induced immunosuppression, supporting that pro-tumoral metabolic dysregulation is directly linked to angiogenesis. In GBM, hypoxia and tryptophan–kynurenine pathway dysregulation operate as an integrated metabolic circuit that drives widespread immunosuppression. These mechanisms can be captured by a metabolic signature shared across nearly every cell type in the GBM microenvironment. Drawing on recent spatial transcriptomic, metabolomic, and pharmacologic studies, we outline how this metabolic axis shapes disease biology and how it can be targeted to restore effective antitumor immunity.

The kynurenine pathway (KP) and associated catabolites play key roles in promoting tumor progression and modulating the host anti-tumor immune response. To date, considerable focus has been on the role of indoleamine 2,3-dioxygenase 1 (IDO1) and its catabolite, kynurenine (Kyn). However, increasing evidence has demonstrated that downstream KP enzymes and their associated metabolite products can also elicit tumor-microenvironment immune suppression. These advancements in our understanding of the tumor promotive role of the KP have led to the conception of novel therapeutic strategies to target the KP pathway for anti-cancer effects and reversal of immune escape. This review aims to 1) highlight the known biological functions of key enzymes in the KP, and 2) provide a comprehensive overview of existing and emerging therapies aimed at targeting discrete enzymes in the KP for anti-cancer treatment.

… is essential for tumor immunotherapy. Herein, we focus on significant advances in tumor metabolic reprogramming, tumor immune microenvironment (TIME) remodeling, immunotherapy…

The clinical efficacy of immune checkpoint blockade (ICB) therapy is significantly compromised in the metabolically disordered tumor microenvironment (TME), posing a formidable challenge that cannot be ignored in current antitumor strategies. In this study, TME‐responsive nanoparticles (HMP1G NPs) loaded with 1‐methyltryptophan (1‐MT; an indoleamine 2,3‐dioxygenase 1 [IDO1] inhibitor,) and S‐nitrosoglutathione (GSNO; a nitric oxide donor) is developed to enhance the therapeutic efficacy of 1‐MT‐mediated ICB. The HMP1G NPs responded to H+ and glutathione in the TME, releasing Mn2+, GSNO, and 1‐MT. The released Mn2+ catalyzed the production of abundant reactive oxygen species and nitric oxide from hydrogen peroxide and GSNO, and the generated nitric oxide, synergistically with 1‐MT, inhibited the accumulation of kynurenine mediated by IDO1 in the tumor. Mechanistically, HMP1G NPs downregulated tumor cell‐derived IDO1 via the aryl hydrocarbon receptor/signal transducer and activator of transcription 3/interleukin signaling axis to improve kynurenine/tryptophan metabolism and immunosuppression. In a murine breast cancer model, treatment with HMP1G NPs elicited effective antitumor immunity and enhanced survival outcomes. This study highlights a novel nano‐platform that simultaneously improves metabolism and enhances ICB efficacy to achieve a new and efficient antitumor strategy.

… notion that tryptophan catabolism is mechanistically … tryptophan catabolism for understanding the mechanistic basis of some immunoregulatory processes. Why is tryptophan catabolism …

Background Perturbation of tryptophan (TRP) metabolism contributes to the immune escape of cancer; however, the explored TRP metabolites are limited, and their efficacy in clarifying the susceptibility and progression of esophageal cancer (EC) remains ambiguous. Our study sought to evaluate the effects of the TRP metabolic profile on the clinical outcomes of EC using a Chinese population cohort; and to develop a risk prediction model targeting TRP metabolism. Method A total of 456 healthy individuals as control subjects and 393 patients with EC who were followed up for one year as case subjects were enrolled. Quantification of the plasma concentrations of TRP and its metabolites was performed using HPLC-MS/MS. The logistic regression model was applied to evaluate the effects of the clinical characteristics and plasma metabolites of the subjects on susceptibility and tumor metastasis events, whereas Cox regression analysis was performed to assess the overall survival (OS) of the patients. Results Levels of creatinine and liver enzymes were substantially correlated with multiple metabolites/metabolite ratios in TRP metabolism, suggesting that hepatic and renal function would exert effects on TRP metabolism. Age- and sex-matched case–control subjects were selected using propensity score matching. Plasma exposure to 5-HT was found to be elevated 3.94-fold in case subjects (N = 166) compared to control subjects (N = 203), achieving an AUC of 0.811 for predicting susceptibility event. Subsequent correlation analysis indicated that a higher plasma exposure to 5-HIAA significantly increased the risk of lymph node metastasis (OR: 2.16, p = 0.0114). Furthermore, it was figured out that OS was significantly shorter for patients with elevated XA/KYN ratio (HR: 1.99, p = 0.0016), in which medium and high levels of XA/KYN versus low level had a significantly lower OS (HR: 0.48, p = 0.0080 and HR: 0.42, p = 0.0031, respectively). Conclusion This study provides a pivotal basis for targeting endogenous TRP metabolism as a potential therapeutic intervention.

Abstract Tryptophan is an essential amino acid, going through three different metabolic pathways in the intestines. Indole pathway in the gut microbiota, serotonin system in the enterochromaffin cells and kynurenine pathway in the immune cells and intestinal lining are the three arms of tryptophan metabolism in the intestines. Clinical, in vivo and in vitro studies showed that each one of these arms has a significant impact on IBD. This review explains how different metabolites of tryptophan are involved in the pathophysiology of IBD and colorectal cancer, as a major complication of IBD. Indole metabolites alleviate colitis and protect against colorectal cancer while serotonin arm follows a more complicated and receptor-specific pattern. Indole metabolites and kynurenine interact with aryl hydrocarbon receptor (AHR) to induce T regulatory cells differentiation, confine Th17 and Th1 response and produce anti-inflammatory mediators. Kynurenine decreases tumor-infiltrating CD8+ cells and mediates tumor cells immune evasion. Serotonin system also increases colorectal cancer cells proliferation and metastasis while, indole metabolites can profoundly decrease colorectal cancer growth. Targeted therapy for tryptophan metabolites may improve the management of IBD and colorectal cancer, e.g. supplementation of indole metabolites such as indole-3-carbinol (I3C), inhibition of kynurenine monooxygenase (KMO) and selective stimulation or inhibition of specific serotonergic receptors can mitigate colitis. Furthermore, it will be explained how indole metabolites supplementation, inhibition of indoleamine 2,3-dioxygenase 1 (IDO1), KMO and serotonin receptors can protect against colorectal cancer. Additionally, extensive molecular interactions between tryptophan metabolites and intracellular signaling pathways will be thoroughly discussed.