{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T09:12:05Z","timestamp":1790327525925,"version":"4.1.0"},"reference-count":144,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":13,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp; Translational Med"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Tryptophan metabolism drives colorectal cancer (CRC) pathogenesis through three interconnected cascades: the kynurenine pathway, the serotonin pathway, and the gut\u2010microbiota\u2010dominated indole pathway. These pathways exert context\u2010dependent dual activities determined by disease stage, metabolite concentration, cell type and tumor microenvironment. Substrate competition and metabolic flux redistribution occur across the three branches, while extra\u2010intestinal tryptophan metabolites mediate multi\u2010organ crosstalk. Despite substantial preclinical findings, clinical translation is hindered by imperfect predictive biomarkers, therapeutic bypass resistance and insufficient causal evidence for the microbiota\u2010metabolite\u2010host axis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Main body<\/jats:title>\n                    <jats:p>This review summarizes biotransformation features and substrate\u2010competing networks of tryptophan metabolism. The kynurenine pathway, responsible for approximately 95% of systemic tryptophan catabolism, exerts stage\u2010dependent dual roles. Its plasma\u2010 and feces\u2010derived metabolites and rate\u2010limiting enzyme indoleamine 2,3\u2010dioxygenase\u00a01 show diagnostic and prognostic potential, yet monotherapies targeting this enzyme yield poor outcomes due to interleukin\u20104\u2010induced gene\u00a01\u2010mediated bypass resistance. The serotonin pathway accounts for only 1%\u20102% of tryptophan flux; it is predominantly tumor\u2010promoting and protective solely in early\u2010phase colitis\u2010associated tumorigenesis. Selective serotonin reuptake inhibitors hold promise for chemoprevention and immunotherapy sensitization. The microbiota\u2010governed indole pathway generates diverse compounds: indole\u20103\u2010lactic acid, indole\u20103\u2010acetic acid and indole\u20103\u2010propionic acid boost programmed cell death protein\u00a01 (PD\u20101)\u2010based therapeutic efficacy; indole\u20103\u2010acrylic acid and 3\u2010methylindole facilitate tumor progression; indole\u20103\u2010acetaldehyde displays concentration\u2010dependent bidirectional effects. We also discuss natural\u2010product\u2010based and microbiota\u2010targeted interventions, as well as key experimental bottlenecks.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Preclinical metabolite\u2010guided personalized therapy for CRC requires multi\u2010omics, stable\u2010isotope tracing and organoid\u2010based large\u2010scale prospective cohorts. Standardized patient stratification and clarification of causal metabolic networks are urgently needed.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.70831","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T23:56:42Z","timestamp":1789430202000},"source":"Crossref","is-referenced-by-count":0,"title":["Tryptophan metabolism in colorectal cancer: From mechanistic insights to novel therapeutic strategies"],"prefix":"10.1002","volume":"16","author":[{"given":"Ran","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Gastroenterology The First Affiliated Hospital of Ningbo University  Ningbo Zhejiang Province China"},{"name":"Health Science Center Ningbo University  Ningbo Zhejiang Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenke","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology The First Affiliated Hospital of Ningbo University  Ningbo 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