High-grade
gliomas are
primary brain tumors that are incredibly refractory long-term to surgery and chemoradiation, with no proven durable
salvage therapies for patients that have failed conventional treatments. Post-treatment, the latent
glioma and its microenvironment are characterized by a senescent-like state of mitotic arrest and a senescence-associated secretory phenotype (SASP) induced by prior chemoradiation. Although senescence was once thought to be irreversible, recent evidence has demonstrated that cells may escape this state and re-enter the cell cycle, contributing to
tumor recurrence. Moreover, senescent
tumor cells could spur the growth of their non-senescent counterparts, thereby accelerating recurrence. In this review, we highlight emerging evidence supporting the use of
senolytic agents to ablate latent, senescent-like cells that could contribute to
tumor recurrence. We also discuss how senescent cell clearance can decrease the SASP within the tumor microenvironment thereby reducing
tumor aggressiveness at recurrence. Finally,
senolytics could improve the long-term sequelae of prior
therapy on cognition and bone marrow function. We critically review the senolytic drugs currently under preclinical and clinical investigation and the potential challenges that may be associated with deploying
senolytics against latent
glioma. In conclusion, senescence in
glioma and the microenvironment are critical and potential targets for delaying or preventing
tumor recurrence and improving patient functional outcomes through
senotherapeutics.