Simple Summary
Prostate cancer can become difficult to treat when it adapts to therapy and spreads, leading to treatment-resistant disease. A key reason for this is that cancer cells do not act alone: they are supported by nearby “helper” cells that shape the tumor environment. Among these, cancer-associated fibroblasts can build a dense scaffold around tumors, release signals that fuel cancer growth, and weaken immune responses, which may reduce the effectiveness of medicines. This review aims to explain what these fibroblasts are, how they change during prostate cancer progression, and why different fibroblast types may require different treatment approaches. By summarizing recent biological insights and emerging therapeutic strategies, we highlight how targeting the tumor-supporting environment—rather than cancer cells alone—could help design more effective combination treatments and guide future research toward more personalized care.
Abstract
Advanced prostate cancer, particularly castration-resistant disease, remains challenging to treat due to intratumoral heterogeneity, immune exclusion, and a suppressive tumor microenvironment. Within this ecosystem, cancer-associated fibroblasts shape tumor–stroma communication, but their marked heterogeneity and plasticity complicate classification and make indiscriminate fibroblast depletion potentially ineffective or even harmful. This review summarizes recent progress in fibroblast origins, functional subtypes, and fibroblast-driven mechanisms that promote tumor progression and therapy resistance, as well as emerging therapeutic opportunities in prostate cancer. We conducted a structured literature search of PubMed, ScienceDirect, and major publisher platforms (including Nature and SpringerLink) from database inception to 15 February 2025, supplemented by targeted manual screening of reference lists. Evidence from single-cell/spatial-omics and mechanistic studies indicates that prostate tumors contain multiple fibroblast programs that occupy distinct niches yet can interconvert. Across these studies, it was found that these fibroblasts contribute to immune suppression, extracellular matrix remodeling and stromal barrier formation, angiogenesis, and metabolic support, collectively limiting drug penetration and reinforcing immune evasion; therapeutic pressure can further rewire fibroblast states and resistance-associated signaling. Overall, the literature supports a shift toward function- and subtype-directed intervention rather than “one-size-fits-all” targeting, with promising directions including precision targeting and reversible reprogramming, rational combination strategies, and localized delivery approaches that reduce stromal barriers while preserving tissue homeostasis in high-risk and treatment-refractory prostate cancer.