Gut microbiota-derived metabolites in gastrointestinal cancer: immunomodulatory mechanisms via the tryptophan–AhR axis and translational perspectives

The gut microbiota contributes to host physiological homeostasis through the production of diverse bioactive metabolites that orchestrate immune responses, maintain intestinal barrier integrity, and regulate metabolic signaling. Increasing evidence indicates that these microbiota-derived metabolites act as critical mediators linking microbial composition to gastrointestinal tumorigenesis. Among them, short-chain fatty acids (SCFAs), bile acids, and amino acid-derived metabolites-particularly tryptophan metabolites-have been most extensively studied. These metabolites influence tumor initiation and progression via multiple mechanisms, including modulation of inflammatory responses, epigenetic remodeling, control of cell proliferation and apoptosis, and reprogramming of the tumor microenvironment (TME). This review provides a systematic overview of the sources, biological functions, and mechanistic roles of major gut microbial metabolites in gastrointestinal cancer. We emphasize three interconnected regulatory axes: inflammation-immunity modulation, intestinal barrier homeostasis, and metabolism-epigenetic reprogramming, while highlighting the tryptophan-aryl hydrocarbon receptor (AhR) axis as a central immunoregulatory hub. SCFAs generally exert protective effects by reinforcing epithelial barrier function and supporting anti-tumor immunity, whereas bile acids display context-dependent duality, with secondary bile acids being closely associated with chronic inflammation, DNA damage, and colorectal cancer progression. Tryptophan metabolites primarily shape mucosal immunity and tumor immune escape through activation of AhR signaling. Despite substantial progress, important challenges remain, including incomplete causal understanding, marked inter-individual variability, and limited clinical translation. Future studies integrating multi-omics approaches, single-cell and spatial technologies, and prospective clinical validation will be essential for defining key metabolite networks and advancing metabolite-based biomarkers and precision therapeutic strategies.