Nucleo-cytosolic acetyl-CoA drives tumor immune evasion by regulating PD-L1 in melanoma
Huina Wang, Xiuli Yi, Xiangxu Wang, Yuqi Yang, Hengxiang Zhang, Hao Wang, Jianru Chen, Baolu Zhang, Sen Guo, Lili Wu, Juan Du, Yuhan Chen, Ningyue Sun, Tianwen Gao, Rui Zhang, Huijie Bian, Lintao Jia, Chunying Li, Weinan Guo
Abstract
Acetyl coenzyme A (acetyl-CoA), a versatile central metabolite, plays a critical role in various metabolic processes and protein acetylation. While its impact on tumor cell properties is well established, the connection between acetyl-CoA metabolism and immune evasion in tumors remains unclear. Here, we uncover a mechanism by which nucleo-cytosolic acetyl-CoA contributes to immune evasion through regulation of programmed death ligand 1 (PD-L1). Specifically, bioinformatics analysis reveals a negative correlation between acetyl-CoA metabolism and anti-tumor immunity across multiple cancers. Inhibition of the acetyl-CoA-producing enzyme ATP-citrate lyase (ACLY) leads to a re-invigoration of cytotoxic T cells and enhances the efficacy of immunotherapy. Mechanistically, nucleo-cytosolic acetyl-CoA promotes PD-L1 transcription via P300-dependent histone H3K27 acetylation at the promoter region of CD274. The ACLY-H3K27ac-PD-L1 axis is verified in clinical specimens and predicts poor immunotherapy response. Our findings suggest that targeting acetyl-CoA metabolism may act as a promising strategy to overcome immune evasion and improve the outcomes of cancer immunotherapy.