Cancer stem cell plasticity in shaping drug resistance landscapes in prostate cancer

Prostate-related diseases exhibit an extremely high incidence among aging males, including Benign Prostatic Hyperplasia (BPH) and prostate Cancer (PCa). Prostate stem cells are critical for prostate development, adult tissue homeostasis, and injury repair, and are also considered potential cells of origin for tumorigenesis. Recent studies have demonstrated that various prostate stem cell populations serve as key drivers in both the initiation and progression of prostatic diseases, while also contributing to therapy resistance. Consequently, prostate stem cells have emerged as promising therapeutic targets for both fundamental research and clinical translational studies.

This review provides a comprehensive summary of the identity and characteristics of various prostate epithelial stem cells, elaborating on the cell fate and function of different prostate stem cells under both physiological and pathological conditions. Additionally, the review offers theoretical evidence linking the lineage plasticity of prostate stem cells to the drug resistance observed in prostate diseases, and critically discusses both the limitations and therapeutic potential of emerging stem cell-targeting strategies.

This review integrates contemporary knowledge regarding the identity and cellular plasticity of prostate stem cell subpopulations across physiological and pathological contexts, encompassing prostate development, tissue homeostasis, inflammatory responses, and oncogenesis. These stem cells demonstrate critical adaptability to microenvironmental challenges, underpinning essential functions in epithelial regeneration, neoplastic initiation, and tumor evolution. Significantly, their capacity to dynamically reprogram cellular fate trajectories has been shown to fundamentally underpin mechanisms of therapeutic evasion, fostering the emergence of treatment resistance. Collectively, these insights position the molecular targeting of prostate stem cells as a novel therapeutic paradigm for managing advanced prostate malignancies.