From microbial dysbiosis to immune evasion: evidence and emerging mechanisms of gut microbiota-mediated modulation of PD-1/PD-L1 efficacy in genitourinary malignancies

Immune checkpoint inhibitors targeting the PD-1/PD-L1 axis have transformed the treatment landscape for genitourinary malignancies, yet primary and acquired resistance remains a substantial clinical obstacle. The gut microbiome has emerged as a critical determinant of immunotherapy efficacy, with dysbiosis driving immune evasion through disruption of metabolite-mediated signaling, impairment of intestinal barrier function, and systemic immunosuppression. This review synthesizes current mechanistic understanding of how gut microbial metabolites, including short-chain fatty acids, tryptophan catabolites, and bile acids, modulate PD-1/PD-L1 expression via epigenetic reprogramming, aryl hydrocarbon receptor activation, and T cell functional modulation. Specific bacterial taxa such as Akkermansia muciniphila and Blautia coccoides enhance antitumor immunity through distinct molecular pathways, while the genitourinary microbiome exerts local immunomodulatory effects. Clinical evidence supporting microbiome-based candidate biomarkers associated with ICIs outcomes and emerging therapeutic strategies including fecal microbiota transplantation, probiotics, and dietary interventions are critically evaluated. This review distinguishes direct genitourinary-specific evidence from cross-cancer mechanistic evidence and provides a unified framework for understanding the microbiome-immunity axis and its translational potential in genitourinary oncology.