Gut microbiota-mediated chemotherapy resistance in colorectal cancer: mechanisms and precision interventions.

Colorectal cancer (CRC) is a major global health burden, and chemotherapy resistance remains a major challenge to effective treatment. Increasing evidence indicates that the gut microbiota may contribute to variability in chemotherapy response in CRC through microbial metabolism, tumor-cell adaptation, immune regulation, and microbiota-derived metabolites. These processes can alter drug exposure, cellular stress responses, antitumor immunity, and metabolic conditions within the tumor-host ecosystem. In this review, we summarize current evidence on the mechanisms linking the gut microbiota to chemotherapy response in CRC, focusing on microbial drug metabolism, tumor-cell adaptation, immune and metabolic regulation, and microbial interactions with host signaling pathways. We also discuss emerging microbiome-based interventions, including probiotics, fecal microbiota transplantation, phage therapy, and targeted modulation of microbial functions, while considering the limitations of current evidence and challenges to clinical translation. Finally, we highlight future priorities, including causal validation of microbial functions, identification of robust biomarkers, and prospective evaluation of microbiome-informed patient stratification. This review provides an overview of current mechanistic evidence and the potential of microbiome-based approaches to improve chemotherapy response in CRC.