Unravelling therapeutic resistance: role of cancer stem cell and microRNA in metastatic prostate cancer.

Metastatic prostate cancer (PCa) is one of the leading causes of cancer-related deaths in men globally. This is largely attributable to the occurrence of therapeutic resistance that reduces the efficacy of the traditional treatment, such as Androgen deprivation therapy, chemotherapy, and radiotherapy. Accumulating evidence suggests that prostate cancer stem cells a rare population of Cancer Stem Cells drive therapy resistance by sustaining self-renewal, tumor plasticity, epithelial-mesenchymal transition, and metastasis. Concurrently, miRNAs are critical post-transcriptional regulators of gene expression, modulating key signalling pathways that control CSC stemness, reshaping tumor microenvironment, and conferring resistance to therapy. Dysregulation of miRNAs has been closely associated with the regulation of CSCs and the progression of metastatic PCa, and causes disease recurrence. In accordance with their targets, miRNAs can function either as oncogenic drivers that promote cancer progression or as tumor suppressors that inhibit malignant transformation and growth. Moreover, it contributes to the capacity of CSCs to withstand therapy and initiate disease recurrence. Recent advances in precision oncology have increased the pace of novel therapeutic modalities, such as CRISPR/Cas9, nanotechnology-based delivery vehicles, chimeric antigen receptor -T cell therapy, and epigenetic reprogramming strategies to counteract aberrant transcriptional states that sustain PCSC plasticity. The integration of these approaches offers a promising strategy to overcome refractoriness to treatment and improve clinical outcomes in advanced PCa. This review highlights the complex interplay between miRNAs and PCSCs in therapy resistance of metastatic PCa, and explores their translational potential in shaping durable and more effective clinical interventions.