Prostate cancer stem cell dynamics in the evolution of drug resistance

Prostate cancer remains a leading cause of cancer-related mortality in men worldwide, with tumor heterogeneity, therapy resistance, and lineage plasticity posing significant clinical challenges. Androgen deprivation therapy (ADT), while initially effective, often culminates in castration-resistant prostate cancer, may fueled by castration-resistant prostate cancer stem cells (CSCs) with adaptive self-renewal and regenerative capacities. Emerging evidence implicates prostate CSCs as pivotal contributors to tumor heterogeneity, drug resistance, and disease recurrence. These stem subpopulations exhibit intrinsic adaptability through genetic, epigenetic, and microenvironmental reprogramming, enabling survival under androgen-deprived conditions and fostering clonal diversification. This review synthesizes current knowledge on the identity, regulation, and functional dynamics of prostate stem cells, emphasizing their role in shaping the tumor ecosystem. By dissecting the genetic drivers, epigenetic alteration and crosstalk with microenvironment, this review underscores critical triggers on prostate CSCs determination and differentiation. Additionally, we discuss emerging strategies to target prostate CSC-specific vulnerabilities, including molecular drivers of stemness and plasticity, to improve therapeutic outcomes for advanced prostate malignancies. This synthesis underscores the critical need to unravel prostate stem cells biology for developing precision therapies against prostate CSC-driven adaptation in prostate diseases.