Immune Checkpoint Inhibitor Resistance in Genitourinary Cancers: Mechanisms, Biomarkers, and Emerging Therapeutic Strategies

Immune checkpoint inhibitors (ICI) targeting the programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) axes have transformed the treatment landscape of genitourinary (GU) malignancies, yielding durable responses in subsets of patients with urothelial carcinoma, renal cell carcinoma (RCC), and selected cases of metastatic castration-resistant prostate cancer (mCRPC). However, most patients exhibit primary resistance, and those who initially respond frequently develop acquired resistance, substantially limiting long-term clinical benefit. A systematic understanding of the biological mechanisms driving resistance, the identification of robust predictive biomarkers, and the design of rational combination strategies are essential to extend the therapeutic reach of ICI-based regimens. To address this need, an integrative review was conducted following the Whittemore and Knafl (2005) framework. Systematic searches were performed in PubMed/MEDLINE, Cochrane Central Register of Controlled Trials, Embase, and Web of Science, covering the period January 2020 to April 2026. Studies were selected according to predefined inclusion criteria encompassing original research, clinical trials, systematic reviews, and narrative reviews reporting on resistance mechanisms, predictive biomarkers, or emerging therapeutic strategies for ICI in GU cancers. A total of 32 studies met eligibility criteria. Three interconnected resistance categories were identified: (1) tumor cell-intrinsic mechanisms, including low tumor mutational burden (TMB), loss of antigen presentation via major histocompatibility complex class I (MHC-I) downregulation, activation of the Wnt/β-catenin and JAK/STAT pathways, and epigenetic reprogramming; (2) tumor microenvironment (TME)-mediated immunosuppression, driven by myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), cancer-associated fibroblasts (CAFs), and immunosuppressive cytokines including TGF-β and vascular endothelial growth factor (VEGF); and (3) acquired post-treatment resistance involving T-cell exhaustion and upregulation of alternative immune checkpoints. Among validated or clinically used biomarkers, PD-L1 expression demonstrated variable predictive utility across GU cancer types, while TMB-high status (≥10 mutations/megabase) predicted improved response to pembrolizumab across solid tumors. Emerging therapeutic strategies include ICI plus tyrosine kinase inhibitor (TKI) combinations, antibody-drug conjugates (ADCs), MDSC-targeted interventions, therapeutic vaccines, and radiotherapy sensitization. Overall, ICI resistance in GU cancers emerges as a multidimensional phenomenon with distinct biological drivers across tumor subtypes; precision combinations targeting both intrinsic tumor factors and the immunosuppressive TME represent the most promising avenue to overcome resistance, and standardization of composite biomarker platforms is urgently needed to individualize ICI selection in clinical practice.