The expression, regulation, and function of human endogenous retroviruses in genitourinary cancers

Abstract Human endogenous retroviruses (HERVs), constituting approximately 8% of the human genome, represent genomic remnants of ancestral retroviral infections that colonized the germline through evolutionary processes. While most HERVs remain epigenetically silenced, their reactivation through environmental stimuli or epigenetic dysregulation enables participation in oncogenesis via viral mimicry, immunomodulation, and insertional mutagenesis. Substantial evidence now implicates aberrant HERVs activity across urologic malignancies—including prostate cancer, renal cell carcinoma (RCC), bladder cancer, and testicular germ cell tumors—where cancer-type-specific mechanisms drive tumor development and progression. These encompass androgen-responsive HERV-K activation in prostate malignancies, hypoxia-inducible factor-mediated ERV immunogenicity in RCC, HERV-derived microRNA silencing of tumor suppressors in bladder cancer, and DNA hypomethylation-associated HERV expression in testicular germ cell tumors. This review synthesizes fundamental HERV biology with recent advances in their diagnostic and therapeutic applications for urologic neoplasms. Key clinical translations include ERV-based stratification models predicting immune checkpoint inhibitor response in metastatic RCC, HERV-E-targeted adoptive T cell therapies, and noncoding RNA biomarkers for early bladder cancer detection. We further discuss unresolved mechanistic paradoxes such as contradictory prognostic associations between HERV superfamily expression and PBRM1 inactivation in RCC, concluding with priorities for future research: validating HERV-derived neoantigens in immunotherapy platforms, optimizing epigenetic priming strategies to enhance viral mimicry effects, and establishing standardized HERV signatures as clinical biomarkers through multi-institutional cohorts.