ZBP1-MLKL necroptotic signaling potentiates radiation-induced antitumor immunity via intratumoral STING pathway activation
| Autor: | Lingling Wu, Yuanqin Yang, Dongqing Cao, Chao Yang, Meng Wu, Zhen Zhang, Xinran Wang, Youqiong Ye, Jinmei Li, Hui Xiao, Liufu Deng, Lu Lu, Xiangjiao Meng, Jinming Yu, Jingsi Jin, Jinke Cheng, Xiaochuan Hong, Wenwen Li |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: | |
| Zdroj: | Science Advances |
| ISSN: | 2375-2548 |
| Popis: | Description ZBP1-MLKL necroptotic signaling bridges tumor cell damage to antitumor immune responses after radiation. Necroptosis, a form of regulated necrosis, participates in tumor development and dying cell immunogenicity. However, it remains unclear how tumor cell–intrinsic necroptotic signaling contributes to radiation-induced antitumor immunity. Here, we found that the ZBP1-MLKL necroptotic cascade in irradiated tumor cells was essential for antitumor immunity. ZBP1-dependent activation of MLKL potentiated type I interferon responses following tumor cell irradiation. Mechanistically, the ZBP1-MLKL necroptotic cascade induced cytoplasmic DNA accumulation in irradiated tumor cells and, in turn, autonomously activated cGAS-STING signaling, thus creating a positive feedback loop between those two pathways to drive persistent inflammation. Accordingly, ablation of caspase-8 enhanced STING pathway activation and the antitumor effects of radiation by activating MLKL. These findings reveal that ZBP1-MLKL necroptosis signaling maximized radiation-induced antitumor immunity through mutual interaction with the tumor cell–intrinsic STING pathway. This study provides insight into how radiotherapy bridges tumor cell damage to antitumor immune responses and an alternative strategy to improve radiotherapy. |
| Databáze: | OpenAIRE |
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