Tryptophan metabolism in colorectal cancer: From mechanistic insights to novel therapeutic strategies.

BACKGROUND: Tryptophan metabolism drives colorectal cancer (CRC) pathogenesis through three interconnected cascades: the kynurenine pathway, the serotonin pathway, and the gut-microbiota-dominated indole pathway. These pathways exert context-dependent 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-intestinal tryptophan metabolites mediate multi-organ crosstalk. Despite substantial preclinical findings, clinical translation is hindered by imperfect predictive biomarkers, therapeutic bypass resistance and insufficient causal evidence for the microbiota-metabolite-host axis.

MAIN BODY: This review summarizes biotransformation features and substrate-competing networks of tryptophan metabolism. The kynurenine pathway, responsible for approximately 95% of systemic tryptophan catabolism, exerts stage-dependent dual roles. Its plasma- and feces-derived metabolites and rate-limiting enzyme indoleamine 2,3-dioxygenase 1 show diagnostic and prognostic potential, yet monotherapies targeting this enzyme yield poor outcomes due to interleukin-4-induced gene 1-mediated bypass resistance. The serotonin pathway accounts for only 1%-2% of tryptophan flux; it is predominantly tumor-promoting and protective solely in early-phase colitis-associated tumorigenesis. Selective serotonin reuptake inhibitors hold promise for chemoprevention and immunotherapy sensitization. The microbiota-governed indole pathway generates diverse compounds: indole-3-lactic acid, indole-3-acetic acid and indole-3-propionic acid boost programmed cell death protein 1 (PD-1)-based therapeutic efficacy; indole-3-acrylic acid and 3-methylindole facilitate tumor progression; indole-3-acetaldehyde displays concentration-dependent bidirectional effects. We also discuss natural-product-based and microbiota-targeted interventions, as well as key experimental bottlenecks.

CONCLUSION: Preclinical metabolite-guided personalized therapy for CRC requires multi-omics, stable-isotope tracing and organoid-based large-scale prospective cohorts. Standardized patient stratification and clarification of causal metabolic networks are urgently needed.