2. Academic Validation
  3. Nucleo-cytosolic acetyl-CoA drives tumor immune evasion by regulating PD-L1 in melanoma

Nucleo-cytosolic acetyl-CoA drives tumor immune evasion by regulating PD-L1 in melanoma

  • Cell Rep. 2024 Dec 24;43(12):115015. doi: 10.1016/j.celrep.2024.115015.
Huina Wang 1,  Xiuli Yi 2,  Xiangxu Wang 3,  Yuqi Yang 2,  Hengxiang Zhang 2,  Hao Wang 2,  Jianru Chen 2,  Baolu Zhang 2,  Sen Guo 2,  Lili Wu 2,  Juan Du 2,  Yuhan Chen 2,  Ningyue Sun 2,  Tianwen Gao 2,  Rui Zhang 4,  Huijie Bian 5,  Lintao Jia 6,  Chunying Li 7,  Weinan Guo 8
Affiliations

Affiliations

  • 1 Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China; Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
  • 2 Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
  • 3 Department of Oncology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
  • 4 The State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
  • 5 National Translational Science Center for Molecular Medicine & Department of Cell Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
  • 6 Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China. Electronic address: jialth@fmmu.edu.cn.
  • 7 Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China. Electronic address: lichying@fmmu.edu.cn.
  • 8 Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China; Innovation Research Institute, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China; Military Medical Innovation Center, Fourth Military Medical University, Xi'an, Shaanxi 710032, China. Electronic address: guown@fmmu.edu.cn.
PMID: 39602308 DOI: 10.1016/j.celrep.2024.115015
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.

Keywords

ACLY; Acetyl-CoA; CP: Cancer; PD-L1; histone acetylation; immune evasion; melanoma; metabolism.

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