Gut metabolites: key factors in the cross-talk between the gut microbiota and tumor immunotherapy.
This review synthesizes recent research findings and proposes an integrated "microbiota-metabolite-immune-oncology" framework, highlighting how gut-derived metabolites regulate the dynamics of tumor immunity and informing the development of next-generation immunotherapies. Key metabolites-including short-chain fatty acids (SCFAs), bile acids (BAs), trimethylamine N-oxide (TMAO), indole-3-propionic acid (IPA), and urolithin A-exert bidirectional effects on antitumor immunity through multiple mechanisms. These include histone acetylation-driven epigenetic reprogramming, aryl hydrocarbon receptor (AhR)- and farnesoid X receptor (FXR)-mediated metabolic reprogramming, and direct regulation of immune effectors such as CD8+ T cells and myeloid-derived suppressor cells. Emerging evidence highlights specific roles of these metabolites within the tumor microenvironment (TME): microbial dysbiosis can amplify immunosuppressive circuits, whereas targeted enrichment of certain metabolites may enhance the efficacy of immune checkpoint blockade. Integrative multi-omics analyses have revealed the vascular remodeling effect of TMAO and the spatiotemporal heterogeneity of BAs, thereby connecting the gut-liver-tumor axis and achieving overall immune regulation. By mapping a precision-oriented metabolic roadmap, this review identifies underexplored therapeutic avenues-such as metabolite-targeted interventions and engineered probiotics-that, when combined with immune checkpoint inhibitors, may enable personalized, microbiome-based strategies with the potential to improve outcomes in cancer immunotherapy.