Potential Roles of Cellular Senescence and Inflammaging in Prostate Cancer: Aging Microenvironment, Immune Remodeling, and Therapeutic Implications

Abstract

Highlights What are the main findings? Aging reshapes the prostate tumor microenvironment through cellular senescence, chronic inflammation, immune remodeling, stromal dysfunction, vascular aging, and metabolic stress. Senescence-associated secretory programs and immune-aging networks create an inflammaging niche that may influence prostate cancer progression, immune evasion, and therapy response. What are the implications of the main findings? Inflammaging should be considered an active biological context for prostate cancer progression, rather than merely a consequence of chronological aging. Age-appropriate models, biological-aging biomarkers, spatial profiling, and multi-omics approaches are needed to define and therapeutically target inflammaging-associated prostate cancer. Abstract Prostate cancer is common in older men, yet mechanisms linking aging to tumor progression remain incompletely defined. Beyond genetic alterations, aging reshapes the prostate microenvironment through cellular senescence, chronic low-grade inflammation, immune dysfunction, stromal remodeling, metabolic stress, and impaired tissue repair, collectively promoting inflammaging. This persistent inflammatory state may create a permissive niche for tumor initiation, progression, immune evasion, and treatment resistance. Senescent epithelial and stromal cells release cytokines, chemokines, growth factors, matrix-remodeling enzymes, and extracellular vesicles through the senescence-associated secretory phenotype (SASP). In parallel, immune aging alters T-cell subsets, myeloid cells, macrophages, and anti-tumor surveillance. This review summarizes how SASP programs, Th17/Treg imbalance, IL-17/IL-23 signaling, myeloid remodeling, stromal aging, metabolic stress, and immune–stromal–epithelial crosstalk shape prostate cancer biology. We further discuss therapeutic implications, including cytokine modulation, senescence-directed therapy, metabolic intervention, and biomarker-guided strategies. This review highlights key knowledge gaps and proposes a framework for age-aware prostate cancer research, biomarker development, and therapeutic strategies.