期刊
AUTOPHAGY
卷 19, 期 6, 页码 1764-1780出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2022.2155794
关键词
Autophagy; antitumor immunity; glioblastoma multiform; senescence; SASP
类别
Macroautophagy/autophagy is an important cellular survival mechanism in cancer, and its inhibition has potential therapeutic applications. This study found that inhibiting autophagy not only enhanced chemotherapy efficacy in glioblastoma (GBM) but also induced therapy-induced senescence of GBM cells. Additionally, autophagy inhibition altered the profile of senescence-associated secretory phenotype (SASP), leading to enhanced paracrine senescence, polarization of anti-tumor macrophages, and reduced recruitment of pro-tumor neutrophils. This study reveals the functional link between autophagy and senescence and suggests using autophagy blockage for senescence-mediated antitumor immunity.
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.
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