Microbiome-Driven Carcinogenesis and Circulating Microbial Signals in Genitourinary Cancers.

The microbiome is increasingly recognized as a regulator of carcinogenesis, tumor immunity, and response to immune checkpoint inhibitors (ICIs), but its role in genitourinary cancers remains less clearly defined than in melanoma or colorectal cancer. In this review, we summarize evidence that microbiome-related pathways influence urothelial carcinoma (UC) and renal cell carcinoma (RCC) across the continuum from tumor initiation to immunotherapy outcome. We highlight recent preclinical studies showing that gut microbial environments can causally modify urothelial carcinogenesis through carcinogen metabolism, inflammatory priming, and diet-microbiome interactions in N-butyl-N-(4-hydroxybutyl) nitrosamine-based mouse models, including a newly established upper tract urothelial carcinoma mouse model, as well as emerging clinical data indicating that circulating extracellular vesicle (EV)-associated bacterial DNA is associated with tumor immune phenotypes and ICI outcomes in UC and RCC. Because blood is a low-biomass matrix, we use the term "circulating microbial signals" rather than "blood microbiome" and emphasize the need for contamination-aware analysis, careful EV characterization, and external validation. Current evidence supports a framework in which microbiome-related signals connect intestinal ecology, systemic immune tone, tumor immune contexture, and treatment response, while indicating that circulating EV-associated bacterial DNA remains an exploratory biomarker platform.