Prostate cancer is one of the most common malignancies in men, and its global burden continues to rise. Androgen deprivation therapy and other standard treatments can provide substantial disease control, yet advanced tumors may progress to castration-resistant prostate cancer, which is associated with poor outcomes. Preclinical and translational evidence implicates PCSCs in treatment persistence, progression and relapse. The proposed model is that therapeutic pressure can reduce bulk tumor burden while pre-existing or newly acquired stem-like states persist, with tumor-intrinsic signaling and microenvironmental support potentially allowing those states to repopulate the tumor.

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, showing that hormone-receptor status alone cannot define them. Their behavior is also influenced by genomic context, including PTEN loss, TP53 and RB1 alterations, SPOP mutations, and TMPRSS2–ERG rearrangements. These alterations affect the tumor context in which PCSCs arise, but they are not specific markers of PCSC identity. Hypoxia, interactions with stromal cells and inflammatory signaling can also influence these populations.

The review identifies several interconnected pathways as candidate therapeutic targets: PI3K/AKT/mTOR, RAS/MAPK, Hedgehog, Wnt/β-catenin, Hippo, JAK/STAT, Notch, EGFR and hypoxia-driven HIF signaling. Rather than relying on a single molecular target, the review describes a rationale for combining agents that address bulk tumor cells, PCSC-associated survival programs and the niche in which stem-like states persist. Additional experimental strategies include modifying the microenvironment to suppress epithelial-to-mesenchymal plasticity and restoring tumor-suppressive microRNAs. Checkpoint inhibitors, vaccines and CAR-T cells directed against relevant tumor-associated antigens are also considered, but the supplied evidence does not establish that such immune approaches selectively recognize or eliminate PCSCs in patients.

Translation is limited by several unresolved problems. Available PCSC markers do not consistently distinguish stem-like tumor states from other malignant cells, and different experimental models may represent distinct biological states rather than one uniform population. Drug delivery, toxicity and therapeutic escape may also limit treatment effectiveness. Functionally validated biomarkers are therefore needed to determine whether a therapy changes PCSC behavior rather than merely altering marker expression, and appropriately designed combination trials are required to establish whether targeting PCSC-associated states improves durable disease control. The review’s central conclusion is measured: PCSCs are credible contributors to prostate cancer persistence and progression, but the clinical value of selectively targeting them remains an untested hypothesis.

Subject of Research: Experimental approaches for targeting prostate cancer stem-like states associated with therapy resistance and progression.

Article Title: Novel approaches to target prostate cancer stem cells driving therapy resistance and cancer progression

Article References: Alatawi, F. S. (2026). Novel approaches to target prostate cancer stem cells driving therapy resistance and cancer progression. Molecular Biology Reports, 53(1), Article 1770. https://doi.org/10.1007/s11033-026-12948-8

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12948-8

Keywords: prostate cancer, cancer stem-like cells, therapy resistance, castration-resistant cancer, tumor microenvironment, PI3K/AKT/mTOR, Hedgehog signaling, HIF signaling, microRNAs, cancer immunotherapy, Novel, approaches