ATP柠檬酸裂解酶
癌症研究
癌症免疫疗法
多不饱和脂肪酸
生物化学
化学
生物
免疫疗法
免疫系统
药理学
柠檬酸合酶
脂肪酸
酶
免疫学
作者
Wei Xiang,Hongwei Lv,Fuxue Xing,Xiaoyan Sun,Yue Ma,Lu Wu,Guishuai Lv,Qianni Zong,Wei Wang,Qingsheng Yu,Qiyu Feng,Wen Yang,Hongyang Wang
出处
期刊:Science Advances
[American Association for the Advancement of Science (AAAS)]
日期:2023-12-08
卷期号:9 (49)
被引量:6
标识
DOI:10.1126/sciadv.adi2465
摘要
Adenosine 5′-triphosphate citrate lyase (ACLY) is a cytosolic enzyme that converts citrate into acetyl–coenzyme A for fatty acid and cholesterol biosynthesis. ACLY is up-regulated or activated in many cancers, and targeting ACLY by inhibitors holds promise as potential cancer therapy. However, the role of ACLY in cancer immunity regulation remains poorly understood. Here, we show that ACLY inhibition up-regulates PD-L1 immune checkpoint expression in cancer cells and induces T cell dysfunction to drive immunosuppression and compromise its antitumor effect in immunocompetent mice. Mechanistically, ACLY inhibition causes polyunsaturated fatty acid (PUFA) peroxidation and mitochondrial damage, which triggers mitochondrial DNA leakage to activate the cGAS-STING innate immune pathway. Pharmacological and genetic inhibition of ACLY overcomes cancer resistance to anti–PD-L1 therapy in a cGAS-dependent manner. Furthermore, dietary PUFA supplementation mirrors the enhanced efficacy of PD-L1 blockade by ACLY inhibition. These findings reveal an immunomodulatory role of ACLY and provide combinatorial strategies to overcome immunotherapy resistance in tumors.
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