THE ROLE OF TRYPTOPHAN METABOLISM DYSREGULATION IN THE INITIATION AND PROGRESSION OF MALIGNANT NEOPLASMS

Aim. To summarize current data on tryptophan catabolism and the pathophysiological mechanisms involving tryptophan, its enzymes, and metabolites in tumor initiation and progression.

Materials and methods. A comprehensive search for scientific articles published between 2020 and 2026 was conducted using PubMed, eLIBRARY, and Google Scholar databases. The search used keywords in both Russian and English: «tryptophan metabolism», «kynurenine pathway», «serotonin pathway», «indole pathway», «IDO1», «TDO2», «immunosuppression», «carcinogenesis», «cancer». Inclusion criteria: publications containing data on metabolic, molecular and cellular mechanisms of tryptophan and its metabolites in cancer initiation and progression, as well as clinical studies evaluating the predictive and prognostic value of these substances in oncology. Exclusion criteria: articles in languages other than english and russian, reports, study protocols, duplicates and studies with incomplete data.A total of 37 sources were analyzed, including 3 russian publications, all published within the last 5 years.

Results. Tryptophan metabolic reprogramming is recognized as a hallmark biochemical feature of tumor cells. This review synthesizes current findings on the catabolic pathways of this amino acid and the mechanisms by which tryptophan and its metabolites contribute to the initiation and progression of malignant neoplasms. Particular emphasis is placed on the hyperactivation of the kynurenine pathway mediated by the enzymes IDO1 and TDO2, which leads to immunosuppression, chronic inflammation, and the stimulation of metastasis. Furthermore, the dysregulation of the serotonin and indole pathways and their subsequent impact on carcinogenesis and progression are addressed.

Conclusion. The literature analysis highlights the critical pathogenetic role of tryptophan metabolism disorders in tumor progression and immune evasion. Investigating the enzymatic components of the kynurenine cascade provides a strong rationale for developing novel therapeutic strategies aimed at inhibiting IDO1 and TDO2 activity in oncological practice.

1. Yan J., Chen D., Ye Z., et. al. Molecular mechanisms and therapeutic significance of tryptophan metabolism and signaling in cancer. Mol Cancer. 2024 Oct 10. 23(1). 241. doi: 10.1186/s12943-024-02164-y.

2. Liu Z.Q., Ciudad M.T., McGaha T.L. New insights into tryptophan metabolism in cancer. Trends in Cancer. 2025 Jul. 11(7). 629-641. doi: 10.1016/j.trecan.2025.03.008.

3. Gáspár R., Halmi D., Demján V., et. al. Kynurenine pathway metabolites as potential clinical biomarkers in coronary artery disease. Front. Immunol. 2022 Feb 7. 12. 768560. doi: 10.3389/fimmu.2021.768560.

4. Karmakar S., Lal G. Role of serotonin receptor signaling in cancer cells and anti-tumor immunity. Theranostics. 2021 Mar 11. 11. 5296-5312. doi: 10.7150/thno.55986.

5. Holeček M. Serotonin, kynurenine, and indole pathways of tryptophan metabolism in humans in health and disease. Nutrients. 2026 Feb 6. 18(3). 507. doi: 10.3390/nu18030507.

6. Hezaveh K., Shinde R.S., Klötgen A. et al. Tryptophan-derived microbial metabolites activate the aryl hydrocarbon receptor in tumor-associated macrophages to suppress anti-tumor immunity. Immunity. 2022 Feb 8. 55(2). 324-340.e8.

7. Zlatnik E.Yu., Sagakyants A.B., Novikova I.A., Maksimov A.Yu., Shatova O.P. Tryptophan metabolism at different effects of immunotherapy for non-small cell lung cancer with PD-1/PD-L1 inhibitors. Advances in Molecular Oncology. 2022. 9(2). 89-96. doi: 10.17650/2313-805X-2022-9-2-89-96.

8. Asquino A., Cirillo A., Botticelli A. et al. Circulating CD137⁺Treg cells and LOX-1⁺PMN-MDSCs as biomarkers of immunotherapy resistance in (R/M) HNSCC patients. J Exp Clin Cancer Res. 2025 Dec 3. 44(1). 316. doi: 10.1186/s13046-025-03244-z.

9. Zhao Y., Sun J., Li Y., et al. Tryptophan 2,3-dioxygenase 2 controls M2 macrophages polarization to promote esophageal squamous cell carcinoma progression via AKT/GSK3β/IL-8 signaling pathway. Acta Pharm Sin B. 2021 Sep. 11(9). 2835-2849. doi: 10.1016/j.apsb.2021.03.009.

10. Cui Z., Wang D., Zhang Y., et. al. Role of tryptophan metabolism in cancer. Cancer Innov. 2025 Dec. 4(6). e70037. doi: 10.1002/cai2.70037.

11. Badawy A.A. Tryptophan metabolism and disposition in cancer biology and immunotherapy. Biosci Rep. 2022 Nov 30. 42(11). BSR20221682. doi: 10.1042/BSR20221682.

12. Lin Y.J., Wu Y.C., Liu Y.J. et al. Targeting SLC7A5 in lung squamous cell carcinoma: implications for cancer metabolism shift and boron neutron capture therapy resistance. Oncogenesis. 2025 Feb 12. 14. 26. doi: 10.1038/s41389-025-00568-z.

13. Cecchi M., Mannini A., Lapucci A. et al. Dexamethasone promotes a stem-like phenotype in human melanoma cells via tryptophan 2,3 dioxygenase. Front Pharmacol. 2022 Jun 8. 13. 911019. doi: 10.3389/fphar.2022.911019.

14. Zhang J., Guo Z., Xie Q. et al. Tryptophan hydroxylase 1 drives glioma progression by modulating the serotonin/L1CAM/NF-κB signaling pathway. BMC Cancer. 2022 May 6. 22. 457. doi: 10.1186/s12885-022-09569-2.

15. Pham Q.T., Taniyama D., Akabane S. et al. Essential roles of TDO2 in gastric cancer: TDO2 is associated with cancer progression, patient survival, PD-L1 expression, and cancer stem cells. Pathobiology. 2023 Jan. 90(1). 44-55. doi: 10.1159/000523750.

16. Basson C., Serem J.C., Hlophe Y.N., Bipath P. The tryptophan-kynurenine pathway in immunomodulation and cancer metastasis. Cancer Med. 2023 Sep 18. 12(18). 18691-18701. doi: 10.1002/cam4.6484.

17. Zeitler L., Murray P.J. IL4i1 and IDO1: oxidases that control a tryptophan metabolic nexus in cancer. J Biol Chem. 2023 Jun. 299(6). 104827. doi: 10.1016/j.jbc.2023.104827.

18. Yu L., Lu J., Du W. Tryptophan metabolism in digestive system tumors: unraveling the pathways and implications. Cell Commun Signal. 2024 Mar 22. 22(1). 174. doi: 10.1186/s12964-024-01552-7.

19. Fefelova E.V., Saklakova O.A., Maksimenya M.V., et al. Kynurenine pathway metabolites of tryptophan metabolism in the development of angiopathies in diabetes mellitus. Zabaikalsky Medical Bulletin. 2023. 2. 173-189. doi: 10.52485/19986173_2023_2_173.

20. Wang S., van Schooten F.J., Jin H., Jonkers D., Godschalk R. The involvement of intestinal tryptophan metabolism in inflammatory bowel disease identified by a meta-analysis of the transcriptome and a systematic review of the metabolome. Nutrients. 2023 Jul 1. 15(13). 2886. doi: 10.3390/nu15132886.

21. Fomin A.S., Sergeeva S.P. The role of the serotonin pathway of tryptophan metabolism in the development of neuroinflammation in Alzheimer's disease. Problems of Geroscience. 2023. 2. 80-87. doi: 10.37586/2949-4745-2-2023-80-87.

22. Seo S.K., Kwon B. Immune regulation through tryptophan metabolism. Exp Mol Med. 2023 Jul 7. 55(7). 1371-1379. doi: 10.1038/s12276-023-01028-7.

23. Gasaly N., de Vos P., Hermoso M.A. Impact of bacterial metabolites on gut barrier function and host immunity: a focus on bacterial metabolism and its relevance for intestinal inflammation. Front Immunol. 2021 May 26. 12. 658354. doi: 10.3389/fimmu.2021.658354.

24. Xu H., Hu C., Wang Y., et al. Glutathione peroxidase 2 knockdown suppresses gastric cancer progression and metastasis via regulation of kynurenine metabolism. Oncogene. 2023 Jun 15. 42(24). 1994-2006. doi: 10.1038/s41388-023-02708-4.

25. Rankin L.C., Kaiser K.A., de Los Santos-Alexis K., et al. Dietary tryptophan deficiency promotes gut RORγt+ Treg cells at the expense of Gata3+ Treg cells and alters commensal microbiota metabolism. Cell Rep. 2023 Mar 28. 42(3). 112135. doi: 10.1016/j.celrep.2023.112135.

26. Rangel M.V.d.S., Lopes K.G., Qin X., Borges J.P. Exercise-induced adaptations in the kynurenine pathway: implications for health and disease management. Front Sports Act Living. 2025 Jan 15. 7. 1535152. doi: 10.3389/fspor.2025.1535152.

27. Yates B.A. Tryptophan metabolism, exercise and depression. Nat Rev Endocrinol. 2025 Feb. 21. 201. doi: 10.1038/s41574-025-01090-3.

28. Liang F., Wang G.Z., Wang Y. et al. Tobacco carcinogen induces tryptophan metabolism and immune suppression via induction of indoleamine 2,3-dioxygenase 1. Sig Transduct Target Ther. 2022 Oct 8. 7. 311. doi: 10.1038/s41392-022-01127-3.

29. Su X., Gao Y., Yang R. Gut microbiota-derived tryptophan metabolites maintain gut and systemic homeostasis. Cells. 2022 Aug 3. 11(15). 2296. doi: 10.3390/cells11152296.

30. Sun C., Li M., Zhang L. et al. IDO1 plays a tumor-promoting role via MDM2-mediated suppression of the p53 pathway in diffuse large B-cell lymphoma. Cell Death Dis. 2022 Jun 23. 13. 572.

31. Lu Z., Zhang C., Zhang J. et al. The kynurenine pathway and indole pathway in tryptophan metabolism influence tumor progression. Cancer Med. 2025 Mar. 14(6). e70703. doi: 10.1002/cam4.70703.

32. Qin R., Zhao C., Wang C.J. et al. Tryptophan potentiates CD8+ T cells against cancer cells by TRIP12 tryptophanylation and surface PD-1 downregulation. J Immunother Cancer. 2021 Jul 1. 9(7). e002840. doi: 10.1136/jitc-2021-002840.

33. Zhang Q., Zhao Q., Li T. et al. Lactobacillus plantarum-derived indole-3-lactic acid ameliorates colorectal tumorigenesis via epigenetic regulation of CD8+ T cell immunity. Cell Metab. 2023 Jun 6. 35. 943-960.e9.

34. Liu D., Liang C.H., Huang B. et al. Tryptophan metabolism acts as a new anti-ferroptotic pathway to mediate tumor growth. Adv Sci (Weinh). 2023 Jan. 10. 2204006. doi: 10.1002/advs.202204006.

35. Fong W., Li Q., Ji F. et al. Lactobacillus gallinarum-derived metabolites boost anti-PD1 efficacy in colorectal cancer by inhibiting regulatory T cells through modulating IDO1/kyn/AHR axis. Gut. 2023 Dec. 72. 2272-2285.

36. Perez-Castro L., Garcia R., Venkateswaran N. et al. Tryptophan and its metabolites in normal physiology and cancer etiology. FEBS J. 2023 Jan. 290(1). 7-27. doi: 10.1111/febs.16245.

37. Konopelski P., Mogilnicka I. Biological effects of indole-3-propionic acid, a gut microbiota-derived metabolite, and its precursor tryptophan in mammals' health and disease. Int J Mol Sci. 2022 Jan 22. 23(3). 1222. doi: 10.3390/ijms23031222.