Prostate cancer and cellular senescence: focusing on the tumor microenvironment

Abstract Cellular senescence has emerged as a critical yet context-dependent regulator of prostate cancer (PCa) progression. While senescence initially acts as a tumor-suppressive barrier by enforcing stable cell-cycle arrest and promoting immune-mediated clearance of damaged or premalignant cells, its persistent accumulation can paradoxically facilitate tumor progression. This functional switch is largely mediated by the senescence-associated secretory phenotype (SASP), a complex secretome composed of inflammatory cytokines, chemokines, growth factors, extracellular vesicles, and matrix-remodeling enzymes. Through these mediators, senescent cells actively reshape the tumor microenvironment (TME), thereby promoting chronic inflammation, extracellular matrix remodeling, angiogenesis, cancer stemness, immune evasion, and therapeutic resistance. In PCa, these effects involve multiple stromal and immune components, including cancer-associated fibroblasts, myeloid-derived suppressor cells, tumor-associated macrophages, regulatory T cells, endothelial cells, and non-cellular matrix elements. Therapy-induced senescence further adds complexity, as it may transiently suppress tumor growth but also contribute to disease relapse, lineage plasticity, and progression toward castration-resistant prostate cancer when senescent cells persist. In this review, we summarize the molecular basis of cellular senescence in PCa and discuss how senescence-driven TME remodeling influences tumor behavior. We also highlight emerging therapeutic strategies targeting senescent cells or the SASP, including senolytic and senomorphic, as potential avenues to improve PCa management.