The paradox of cellular senescence in prostate cancer: from tumor suppression to tumor promotion.

Cellular senescence is a fundamental biological program that enforces a stable cell-cycle arrest in response to diverse stresses, acting as a crucial barrier against malignant transformation. In the context of prostate cancer, however, this protective mechanism paradoxically exhibits tumor-promoting potential under certain microenvironmental and therapeutic conditions. This review examines the various aspects of senescence in prostate cancer development, ranging from DNA damage- and oncogene-induced senescence (p53/p21, PTEN/p16, and RAS/MYC) to treatment-induced senescence following androgen deprivation, radiotherapy, and chemotherapy. While senescence temporarily halts tumor formation via cell-intrinsic checkpoints and immune surveillance, overly persistent senescent cells trigger the development of a senescence-associated secretory phenotype (SASP) in which they secrete proinflammatory cytokines, chemokines, and proteases that modify the tumor microenvironment in ways that encourage inflammation, assist in the hyper-epithelial plasticity, and therapeutic resistance of the tumor. This review highlights new insights into the epigenetic control and metabolic rewiring that determine the shift between tumor-suppressing senescence and tumor-promoting senescence. This review consolidates the paradox of 'double-edged sword' senescence, delineating that its impact is contextually dependent on the cell, immune environment, and the duration of senescence. Finally, we discuss the predicted therapeutic approaches based on precision oncology to target and alter senescence using senolytics to eradicate aberrant senescent cells and senomorphics to target and adjust SASP. Addressing and regulating the plasticity of senescence is a significant and critical opportunity for improving the prognosis of prostate cancer, as well as guiding next-generation senescence-informed therapeutic approaches.