Prostate Cancer-Associated Fibroblasts: A Review on CAF Functions, Heterogeneity, Resistance Mechanisms, and Future in a Chip

Cancer-associated fibroblasts (CAFs) are key regulators of the prostate tumor microenvironment (TME) with influence on disease progression and therapeutic response. CAFs originate from multiple precursors and retain remarkable plasticity while tumors evolve. Therefore, the CAF pool displays considerable functional heterogeneity, which is well-reflected in complex molecular signatures. However, overlapping biomarker patterns with other stromal subsets make it challenging to identify and assess the role of specific CAF subpopulations. Through reciprocal tumor-stroma interactions, CAFs promote extracellular matrix (ECM) remodeling, angiogenesis, metabolic reprogramming, and immune evasion, collectively fostering an adaptive niche that supports tumor survival, though some CAF subsets have been shown to support anti-tumor response. In prostate cancer (PCa), CAFs promote resistance to androgen receptor pathway inhibitor therapy, chemotherapy, and radiotherapy, emphasizing their potential value as therapeutic targets. However, CAF targeting has shown limited clinical benefit in PCa, due to complex, context-dependent CAF functions that make it challenging to exploit this unique stromal population for therapeutic gain. Recent advances in organ-on-a-chip (OOC) models offer new opportunities to investigate the mechanisms behind TME interactions and evaluate CAF-targeted strategies in physiologically relevant fully humanized environments. This review provides current insights into CAF heterogeneity and therapy resistance in PCa and highlights emerging translational OOC models to guide the development of more effective therapies to disrupt the TME.