Advances and mechanisms of gut microbiota modulation in enhancing immune checkpoint inhibitor efficacy

The gut microbiota is crucial for maintaining human health by regulating immune homeostasis and metabolic function. Immune checkpoint inhibitors (ICIs) have emerged as a cornerstone of cancer immunotherapy, yet their effectiveness is often hampered by treatment resistance and immune-related adverse events (irAEs). Increasing evidence highlights gut microbiota as a critical determinant of ICI efficacy. Here, we summarize the advances from preclinical mouse models and clinical trials to systematically illustrate how gut microbiota modulation strategies, such as fecal microbiota transplantation, specific microorganism supplementation, dietary and lifestyle interventions, and prebiotic/postbiotic supplementation, can enhance ICI therapeutic outcomes and mitigate irAEs. Mechanistically, the gut microbiota shape host immune responses, influencing innate, adaptive, and mucosal immunity, as well as immune checkpoint expression, through microbial translocation, microbiota-derived metabolites, and extracellular vesicles. This review elucidates the intricate interplay between gut microbiota and ICI treatment responses, laying a theoretical groundwork for developing personalized microbiota-based strategies to optimize cancer immunotherapy.