Therapy-induced senescence in prostate cancer: mechanisms, therapeutic strategies, and clinical implications
Luisa F. Guzman Bacca, Julian Brandariz, Francesca Zacchi, Andrea Zivi, Joaquı́n Mateo, David P. Labbé
Abstract
• Prostate cancer constitutes a leading cause of cancer-related mortality in men. • Cellular senescence, a form of cell cycle arrest with secretory phenotype, is a product of anticancer therapies. • Therapy-induced senescence has tumor-suppressive and tumor-promoting effects in prostate cancer. • Senolytics and senomorphics can mitigate the adverse effects of senescence in prostate cancer. • The effectiveness of senescence-targeting therapies in prostate cancer patients requires further investigation. Prostate cancer (PCa) remains a major cause of cancer-related mortality in men, particularly in its advanced and metastatic stages. While various systemic therapies have improved clinical outcomes, therapy resistance and disease progression remain significant challenges. One critical, yet underappreciated, mechanism influencing treatment response is therapy-induced senescence (TIS), a stable form of cell cycle arrest triggered by anticancer treatments. In PCa, TIS can be elicited by chemotherapy, radiotherapy, hormonal therapies, and targeted agents, and is characterized by a complex interplay of tumor-suppressive and tumor-promoting effects, largely mediated through the senescence-associated secretory phenotype (SASP). This review explores the molecular mechanisms of senescence, the diverse therapeutic strategies that induce it, and the dual roles it plays in PCa progression and treatment resistance. We further discuss emerging approaches that combine senescence-inducing therapies with senescence-targeting strategies, such as senolytics and senomorphics, to mitigate the adverse consequences of persistent senescent PCa cells. Finally, we highlight ongoing clinical trials, translational barriers, and future directions in integrating senotherapy into the clinical management of PCa.