Therapy-Induced Senescence (TIS) and SASP: The p53-Mediated Interplay in Cancer Progression and Treatment

Cellular senescence, initially regarded as a potent tumor-suppressive mechanism, is now recognized as a double-edged sword that modulates the hallmarks of cancer. The tumor suppressor p53 typically orchestrates this process to inhibit tumorigenesis; however, mutations in p53 or its regulators can subvert this program, leading to senescence evasion and therapy resistance. In particular, therapy-induced senescence can paradoxically drive tumor progression via the senescence-associated secretory phenotype, which creates a pro-tumorigenic microenvironment dictated by p53-mediated regulation of NF-κB signaling. Here, we explore the p53-mediated senescence–cancer interplay and evaluate emerging therapies, including senolytics and immunotherapies. We propose that strategic modulation of senescence offers a promising paradigm for future anticancer therapy.