Gut microbiota modulation of systemic immunity and cancer immunotherapy: mechanisms, evidence, and therapeutic implications.

The gut microbiota plays a critical role in regulating systemic immune responses and has emerged as a key determinant of therapeutic efficacy and toxicity in cancer immunotherapy. Accumulating evidence indicates that specific microbial taxa and microbiota-derived metabolites modulate antitumor immunity by shaping immune cell maturation, cytokine signaling, and the tumor microenvironment. In particular, gut microbial metabolites such as short-chain fatty acids, bile acids, and inosine influence immune checkpoint inhibitor responses by regulating T-cell activation, dendritic cell function, and immune homeostasis beyond the intestinal compartment. Preclinical and clinical studies have demonstrated that alterations in gut microbiota composition are associated with variability in immunotherapy outcomes, including treatment resistance and immune-related adverse events. Importantly, microbiota-targeted interventions such as dietary modulation, probiotics, prebiotics, antibiotics, and fecal microbiota transplantation have shown promise in enhancing immunotherapy efficacy and reducing toxicity. This review synthesizes current mechanistic insights and clinical evidence linking the gut microbiota to systemic immunity and cancer immunotherapy outcomes, highlighting microbiome modulation as a potential therapeutic adjuvant to optimize immunotherapy response and support precision oncology.