The controversial role of senescence-associated secretory phenotype (SASP) in cancer therapy.

Cellular senescence, characterized by partially irreversible cell cycle arrest, has a dual role in cancer progression via the senescence-associated secretory phenotype (SASP). SASP encompasses a wide range of bioactive chemicals, including cytokines, chemokines, growth factors, and proteases, all of which can have a significant impact on the tumor microenvironment (TME). Initially, SASP can enhance tumor suppression by attracting immune cells and inhibiting cancer cell proliferation, but its long-term presence at TME can promote tumor growth, metastasis, and treatment resistance. Moreover, therapy-induced senescence, a common side effect of cancer treatments, can result in an increase of senescent cells and pro-tumorigenic SASP. Therefore, recent research has highlighted the potential of targeting SASP to improve cancer therapy. Among the therapeutic strategies, senolytic therapies selectively eliminate senescent cells, whereas senomorphic drugs decrease SASP without cytotoxicity, and there is also combined therapy targeting SASP for oncotherapy. Therefore, it is of crucial importance to develop more specific senotherapeutics and investigate the clinical applications of SASP modulation, such as using SASP components as biomarkers for therapy monitoring and personalized medicine. Taken together, understanding the molecular processes of SASP induction and their function in TME, including its heterogeneity across cell types and tissues, and designing personalized treatment are critical for optimizing cancer therapy and improving patient outcomes.