Tumor-specific mechanisms and therapeutic strategies for overcoming immunotherapy resistance in advanced urological tumors

BACKGROUND: Advanced urological tumors, particularly renal cell carcinoma (RCC), urothelial carcinoma (UC), and prostate cancer, remain a major source of cancer morbidity and mortality. Although immune checkpoint inhibitors (ICIs) have reshaped the management of advanced disease, most patients experience limited or non-durable clinical benefit due to primary or acquired resistance. AIM OF THE REVIEW: To summarize the major phenotypes and mechanisms of immunotherapy resistance in advanced urological tumors, and outline mechanism-based strategies that may restore sensitivity and improve the durability of response. KEY SCIENTIFIC CONCEPTS OF THE REVIEW: Immunotherapy resistance is the result of the interplay between tumor-intrinsic alterations, the tumor microenvironment (TME), and host-related systemic determinants. Tumor-intrinsic mechanisms include low tumor antigenicity, defects in antigen processing and presentation pathways, and lineage-specific oncogenic programs such as the von Hippel-Lindau-hypoxia-inducible factor (VHL-HIF) signaling axis in RCC, fibroblast growth factor receptor (FGFR) pathway activation in UC, and androgen receptor (AR)-driven immune suppression in prostate cancer. Microenvironmental resistance is driven by suppressive myeloid and regulatory lymphoid populations, inhibitory cytokine and metabolic circuits, abnormal vasculature, fibrosis, and adaptive upregulation of alternative immune checkpoints. Host factors, including baseline immune competence, human leukocyte antigen (HLA) diversity, and the gut microbiome, further shape treatment efficacy. On this basis, current reversal strategies include multi-checkpoint blockade, rational combinations with targeted agents, chemo-/radio-immunotherapy, TME reprogramming, and microbiome-directed interventions, ideally guided by biomarkers and multi-omics stratification. CONCLUSION: Overall, immunotherapy resistance in urological malignancies is a multifactorial and dynamic process involving tumor, microenvironmental, and host determinants. A comprehensive, mechanism-driven approach integrating biomarker-guided strategies and combination therapies is essential to improve clinical outcomes and achieve durable responses.