STING,an endoplasmic reticulum(ER)transmembrane protein,mediates innate immune activation upon cGAMP stimulation and is degraded through autophagy.Here,we report that activated STING could be transferred between cells to promote antitumor immunity,a process triggered by RAB22A-mediated non-canonical autophagy.Mechanistically,RAB22A engages PI4K2A to generate PI4P that recruits the Atg12-Atg5-Atg16L1 complex,inducing the formation of ER-derived RAB22A-mediated non-canonical autophagosome,in which STING activated by agonists or chemoradiotherapy is packaged.This RAB22A-Induced autophagosome fuses with RAB22A-positive early endosome,generating a new organelle that we name Rafeesome(RAB22A-mediated non-canonical autophagosome fused with early endosome).Meanwhile,RAB22A inactivates RAB7 to suppress the fusion of Rafeesome with lysosome,thereby enabling the secretion of the inner vesicle of the autophagosome bearing activated STING as a new type of extracellular vesicle that we define as R-EV(RAB22A-induced extracellular vesicle).Activated STING-containing R-EVs induce IFNf3 release from recipient cells to the tumor microenvironment,promoting antitumor immunity.Consistently,RAB22A enhances the antitumor effect of the STING agonist diABZI in mice,and a high RAB22A level predicts good survival in nasopharyngeal cancer patients treated with chemoradiotherapy.Our findings reveal that Rafeesome regulates the intercellular transfer of activated STING to trigger and spread antitumor immunity,and that the inner vesicle of non-canonical autophagosome originated from ER is secreted as R-EV,providing a new perspective for understanding the intercellular communication of organelle membrane proteins.

Sun Yat-sen University Cancer Center,State Key Laboratory of Oncology in South China,Collaborative Innovation Center for Cancer Medicine,Guangzhou,Guangdong,China;Department of Interventional Radiology,The Third Affiliated Hospital of Sun Yat-sen University,Guangzhou,Guangdong,China;Department of Abdominal Oncology,The Cancer Center of the Fifth Affiliated Hospital of Sun Yat-sen University,Zhuhai,Guangdong,China;Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education,School of Life Sciences,Peking University,Beijing,China

[1]Ying Gao;Xueping Zheng;Boyang Chang;Yujie Lin;Xiaodan Huang;Wen Wang;Shirong Ding;Weixiang Zhan;Shang Wang;Beibei Xiao;Lanqing Huo;Youhui Yu;Yilin Chen;Run Gong;Yuanzhong Wu;Ruhua Zhang;Li Zhong;Xin Wang;Qiuyan Chen;Song GaoHu;Zhengfan Jiang;Denghui Wei;Tiebang Kang-.Intercellular transfer of activated STING triggered by RAB22A-mediated non-canonical autophagy promotes antitumor immunity)[J].细胞研究（英文版）,2022(12):1086-1104

RAB22A,PI4K2A,PI4P,Atg16L1,Rafeesome,RAB7,IFNf3,diABZI

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