Autophagy inhibition signals through senescence to promote tumor suppression

Abstract

ABSTRACT Macroautophagy/autophagy, a stress-responsive cellular survival mechanism, plays important and context-dependent roles in cancer, and its inhibition has been implicated as a promising cancer therapeutic approach. The detailed mechanisms underlying the function of autophagy in cancer have not been fully understood. In this study, we show that autophagy inhibition promotes both the efficacy of chemotherapy for the treatment of glioblastoma (GBM) and therapy-induced senescence of GBM cells. As a specific cell fate characterized by permanent cell cycle arrest, senescence is also associated with the expression of a panel of specific secreted protein factors known as senescence-associated secretory phenotype (SASP). Intriguingly, we found that autophagy inhibition not only quantitatively enhanced GBM cell senescence but also qualitatively altered the spectrum of SASP. The altered SASP had increased potent activity to induce paracrine senescence of neighboring GBM cells, to skew macrophage polarization toward the anti-tumor M1 state, and to block the recruitment of pro-tumor neutrophils to GBM tumor tissues. Taken together, this study reveals novel functional communication between autophagy and senescence and suggests cancer therapeutic approaches harnessing autophagy blockage in inducing senescence-mediated antitumor immunity.