Tumor microenvironment-driven drug resistance in urologic cancers: mechanisms and therapeutic targets.

Therapeutic resistance remains a major challenge in the management of urologic cancers, including renal cell carcinoma (RCC), bladder cancer (BC), and prostate cancer (PCa). Recent advances highlight the tumor microenvironment (TME) as a critical determinant of treatment failure across various modalities, such as androgen deprivation therapy (ADT), VEGF-targeted therapies, and immune checkpoint inhibitors (ICIs). This review summarizes how distinct TME components-such as cancer-associated fibroblasts (CAFs), extracellular matrix (ECM), immunosuppressive cells, and hypoxic conditions-promote resistance. CAFs drive oncogenic reactivation and epithelial-mesenchymal transition (EMT), while ECM stiffening hinders immune infiltration and facilitates pro-survival signaling. Immune evasion mechanisms include TGF-β-mediated T cell exclusion, regulatory T cell expansion, and adaptive checkpoint upregulation. Hypoxia and metabolic reprogramming further promote cancer stemness and immune suppression through HIF-2α activation, lactate accumulation, and acidification of TME. Targeting these resistance mechanisms requires a multifaceted approach. Promising strategies include ICI combination therapies with anti-angiogenics or TGF-β inhibitors, ECM-modulating agents, and hypoxia-targeted drugs. Novel approaches such as single-cell and spatial transcriptomics, organoid co-culture systems, and TME-derived biomarkers offer new opportunities for patient stratification and therapeutic development. Integrating TME biology into clinical practice is essential to overcome resistance and improve outcomes in urologic oncology.