Targeting LYPLAL1-mediated cGAS depalmitoylation enhances the response to anti-tumor immunotherapy

作者：Yizeng Fan, Yang Gao, Li Nie, Tao Hou, Weichao Dan, Zixi Wang, Tianjie Liu, Yi Wei, Yuzhao Wang, Bo Liu, Taotao Que, Yuzeshi Lei, Jin Zeng, Jian Ma, Wenyi Wei, Lei Li · 发表于：Molecular Cell · 年份：2023 · DOI：10.1016/j.molcel.2023.09.007 · 被引用次数：65 · 研究领域：interferon and immune responses、Immune Cell Function and Interaction、Ubiquitin and proteasome pathways

Cyclic GMP-AMP synthase (cGAS) binds pathogenic and other cytoplasmic double-stranded DNA (dsDNA) to catalyze the synthesis of cyclic GMP-AMP (cGAMP), which serves as the secondary messenger to activate the STING pathway and innate immune responses. Emerging evidence suggests that activation of the cGAS pathway is crucial for anti-tumor immunity; however, no effective intervention method targeting cGAS is currently available. Here we report that cGAS is palmitoylated by ZDHHC9 at cysteines 404/405, which promotes the dimerization and activation of cGAS. We further identified that lysophospholipase-like 1 (LYPLAL1) depalmitoylates cGAS to compromise its normal function. As such, inhibition of LYPLAL1 significantly enhances cGAS-mediated innate immune response, elevates PD-L1 expression, and enhances anti-tumor response to PD-1 blockade. Our results therefore reveal that targeting LYPLAL1-mediated cGAS depalmitoylation contributes to cGAS activation, providing a potential strategy to augment the efficacy of anti-tumor immunotherapy.