Targeting Cellular Senescence in Prostate Cancer: Molecular Landscape and Therapeutic Avenues

Prostate cancer is one of the major causes of cancer morbidity and mortality in men, especially at advanced stages where treatment fails. Despite the fact that the existing treatment options, such as androgen deprivation therapy, chemotherapy, radiotherapy, PARP inhibitors, and targeted agents, can successfully manage the disease progression, resistance and recurrence are frequent. Recent evidence suggests that therapy-induced senescence is dual and context dependent in prostate cancer. Although senescence at first limits tumor cell growth by halting cellular proliferation, senescent cells may nonetheless survive the treatment and cause tumor progression, immune evasion, and therapeutic resistance through the senescence-associated secretory phenotype (SASP). In addition, the senescent tumor cells can avoid the growth arrest through epigenetic reprogramming and metabolic adaptation, re-enter the cell cycle, and develop more aggressive and recurrent disease. This is a comprehensive review of the existing body of knowledge on how standard treatments induce senescence in prostate cancer cells. We cover the biological processes of senescence entry, maintenance, and escape, and the interactions between senescent tumor cells, the tumor microenvironment, and immune modulation. Also, we discuss the role of senescence in minimal residual disease, drug-tolerant persister cells, and dormant disseminated tumor cells, with a particular focus on their role in late relapse and metastasis. Lastly, the review highlights future therapeutic approaches to tackle senescent cells, such as senolytics and senomorphics, and addresses the current challenges of toxicity, biomarker discovery, and translation into clinical use. Future endeavors in the field of therapy-induced senescence can facilitate in devising treatment plans with prudent combination of senescence-based strategies to overcome therapy resistance in prostate cancer.