Novel approaches to target prostate cancer stem cells driving therapy resistance and cancer progression.

Prostate cancer remains one of the most common malignancies in men, and its global burden continues to rise. Although androgen deprivation therapy and other standard treatments can provide substantial disease control, advanced tumors may progress to castration-resistant prostate cancer, which is associated with poor outcomes. Preclinical and translational evidence implicates prostate cancer stem-like cells (PCSCs) in treatment persistence, progression, and relapse, without establishing them as the sole cause of resistance in patients. PCSC-associated states share functional traits with normal stem cells, including self-renewal and survival under stress; reduced androgen receptor activity occurs in some, but not all, stem-like populations. Their behavior is influenced by the genomic context, including PTEN loss, TP53/RB1 alterations, SPOP mutations, and TMPRSS2-ERG rearrangements, as well as hypoxia, stromal interactions, and inflammatory signaling. These alterations are not specific markers of PCSC identity. Multiple interconnected pathways, notably PI3K/AKT/mTOR, RAS/MAPK, Hedgehog, Wnt/β-catenin, Hippo, JAK/STAT, Notch, EGFR, and hypoxia-driven HIF signaling, provide candidate therapeutic targets. Additional strategies include modifying the microenvironment to suppress epithelial-to-mesenchymal plasticity, restoring tumor-suppressive microRNAs, and developing checkpoint inhibitors, vaccines, and CAR-T cells against relevant tumor-associated antigens. Most PCSC-specific evidence remains experimental, even when a pathway-directed agent has clinical activity or regulatory approval in a molecularly selected prostate cancer population. Clinical tumor responses do not by themselves demonstrate selective PCSC depletion. This narrative review distinguishes mechanistic findings from clinical outcomes and considers limitations involving marker specificity, model selection, drug delivery, toxicity, and therapeutic escape. Functionally validated biomarkers and appropriately designed combination trials are needed to determine whether targeting PCSC-associated states can improve durable disease control.