Gut microbiota and metabolites in remodeling the tumor microenvironment and regulating immunotherapeutic efficacy in colorectal cancer.

Immune checkpoint inhibitors (ICIs) benefit patients with mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) colorectal cancer (CRC), but efficacy remains limited in proficient mismatch repair/microsatellite-stable (pMMR/MSS) tumors. This review evaluates how the gut microbiota and microbial metabolites influence CRC development, the tumor microenvironment, and immunotherapy responses, with emphasis on strategies for pMMR/MSS CRC. We reviewed and critically evaluated recent preclinical, translational, and clinical evidence on microbiota-associated metabolic regulation, chronic inflammation, DNA damage, epigenetic reprogramming, microbial biomarkers, and microbiota-targeted interventions. Microbial effects are context dependent and cannot be classified simply as beneficial or harmful.

Short-chain fatty acids, tryptophan derivatives, and secondary bile acids influence epithelial integrity, immune-cell function, tumor metabolism, and epigenetic regulation. Akkermansia muciniphila, Bifidobacterium, and Lactobacillus strains are promising candidates for improving ICI responses.

Notably, tumor-associated bacteria, including Fusobacterium nucleatum and selected Bacteroides taxa, may exert context-dependent and potentially opposing effects depending on strain, metabolite output, host background, and treatment setting. Emerging strategies include dietary modulation, fecal microbiota transplantation, probiotics, engineered bacteria, and rational combination therapies. The gut microbiota is a modifiable component of ICI resistance rather than a sole determinant. Future studies should establish causal mechanisms and develop reproducible, function-based biomarkers through longitudinal multi-omics analyses and prospective clinical validation.