Harnessing Senescence for Antitumor Immunity to Advance Cancer Treatment

Considering the limitations and complexities of the cell-killing-based cancer treatment approaches, one could aim to integrate symbiotic advances in many energy delivery technologies and transformational pieces of evidence in research on senescence and immunomodulators to advance cancer treatment. Although senescent cells contribute to drug tolerance, resistance to therapy, tumorigenesis, maladapting cancer phenotypes, tumor relapse, recurrence, and metastasis, emerging pieces of evidence also demonstrate that acutely induced senescent cells in tumors can elicit a strong and lasting antitumor immune response juxtaposed to the immunologically silent apoptotic cells. This commentary is to help develop an unconventional conceptual framework to advance cancer treatment. Accordingly, it will involve transiently inducing senescent cells in tumors at optimal levels to prime the immune system with radiation, then eliminating senescent cells with senolytics (drugs that specifically eliminate senescent cells) to disrupt their positive feedback accumulation (to prevent tumor maladaptation and adverse effects in healthy cells) and unleash long-lasting antitumor immunity with immunomodulators. The approach is reasonably speculative and will require scientifically rigorous "fit-for-purpose," well-controlled preclinical research and development involving dose and schedule optimization of radiation and drugs, using representative in vitro and in vivo cancer models to obtain high-quality data to proceed to clinical studies.