Gut microbiome-mediated primary and acquired resistance to immune checkpoint inhibitors in MSI-H/dMMR colorectal cancer: mechanisms, biomarkers, and therapeutic implications-a narrative review.

Introduction: Immune checkpoint inhibitors (ICIs) have transformed the management of microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) colorectal cancer (CRC). However, a substantial proportion of patients exhibit primary resistance or eventually develop acquired resistance, highlighting the need for a better understanding of the biological mechanisms influencing therapeutic response. Increasing evidence suggests that the gut microbiome-immune axis is an important regulator of antitumor immunity through complex interactions among microbial communities, microbial metabolites, host immunity, and the tumor microenvironment. Main body: This narrative review summarizes current evidence regarding the role of the gut microbiome-immune axis in mediating primary and acquired resistance to immune checkpoint inhibition in MSI-H/dMMR CRC. We discuss the physiological interactions that maintain immune homeostasis and review the functional mechanisms through which alterations in microbial metabolic pathways, including short-chain fatty acids, bile acids, tryptophan-derived metabolites, inosine, and polyamines, may influence antitumor immune responses. We further examine microbial composition and functional biomarkers associated with immune checkpoint inhibitor response, together with emerging therapeutic strategies aimed at modulating the gut microbiome-immune axis, including dietary interventions, prebiotics, probiotics, selective antimicrobial approaches, fecal microbiota transplantation, live biotherapeutic products, and next-generation precision microbiome engineering. Finally, we discuss current translational challenges and future research priorities required for successful clinical implementation. Conclusion: The gut microbiome-immune axis represents a promising area of investigation for understanding resistance to immune checkpoint inhibition in MSI-H/dMMR CRC. While growing evidence supports its biological relevance, much of the current knowledge remains preclinical or is derived from early-phase clinical studies. Future progress will depend on mechanistic investigation, longitudinal multi-omic microbiome profiling, standardized methodologies, prospective biomarker validation, and the rational development of microbiome-directed therapeutic strategies to support precision immuno-oncology.