ZBP1-MLKL necroptotic signaling potentiates radiation-induced antitumor immunity via intratumoral STING pathway activation.

ABSTRACT: 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 activat

SUBMITTER: Yang Y 

PROVIDER: S-EPMC8494295 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature