2. Academic Validation
  3. Alterations in PD-L1 succinylation shape anti-tumor immune responses in melanoma

Alterations in PD-L1 succinylation shape anti-tumor immune responses in melanoma

  • Nat Genet. 2025 Mar;57(3):680-693. doi: 10.1038/s41588-025-02077-6.
Long Liang # 1 2,  Xinwei Kuang # 1 3,  Yi He # 1 3,  Lin Zhu 1 3,  Poyee Lau 1 3,  Xin Li 2,  Dingan Luo 1 3,  Lan Gong 1 3,  Wenbin Zhou 1 3,  Fanglin Zhang 2,  Xiaowei Liang 1 3,  Zhuofeng Li 1 3,  Bin Hu 2,  Dandan Liu 2,  Tao Ding 4,  Hui Li 1 3,  Shuang Zhao 1 3,  Juan Su 1 3,  Mien-Chie Hung 5,  Jing Liu 6,  Hong Liu 7 8,  Xiang Chen 9 10
Affiliations

Affiliations

  • 1 Department of Dermatology, Xiangya Hospital & School of Life Sciences & Furong Laboratory, Central South University, Changsha, China.
  • 2 Medical Genetics & School of Life Sciences, Central South University, Changsha, China.
  • 3 Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Clinical Research Center for Cancer Immunotherapy, National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, China.
  • 4 Department of Statistical Science, University College London, London, UK.
  • 5 Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Molecular Biology, Research Center for Cancer Biology, Cancer Biology and Precision Therapeutics Center, and Center for Molecular Medicine, China Medical University, Taichung, Taiwan.
  • 6 Medical Genetics & School of Life Sciences, Central South University, Changsha, China. [email protected].
  • 7 Department of Dermatology, Xiangya Hospital & School of Life Sciences & Furong Laboratory, Central South University, Changsha, China. [email protected].
  • 8 Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Clinical Research Center for Cancer Immunotherapy, National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, China. [email protected].
  • 9 Department of Dermatology, Xiangya Hospital & School of Life Sciences & Furong Laboratory, Central South University, Changsha, China. [email protected].
  • 10 Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Clinical Research Center for Cancer Immunotherapy, National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, China. [email protected].
  • # Contributed equally.
PMID: 40069506 DOI: 10.1038/s41588-025-02077-6
Abstract

Tumors undergo metabolic reprogramming to meet the energetic, synthetic and redox demands essential for malignancy, often characterized by increased glycolysis and lactate production. However, the role of Mitochondrial Metabolism in tumor immunity remains unclear. The present study integrates spatial transcriptomics, bulk transcriptomics and proteomics, revealing a strong link between the metabolite succinyl-CoA and tumor immunity as well as the efficacy of anti-programmed cell death protein-1 (PD-1) therapy in patients with melanoma. Elevated succinyl-CoA levels, through α-ketoglutarate or succinate supplementation, enhanced T cell-mediated tumor elimination, both in vitro and in vivo. Mechanistically, succinylation of the ligand of PD-1 (PD-L1) at lysine 129 led to its degradation. Increased carnitine palmitoyltransferase 1A (CPT1A), identified as a succinyltransferase for PD-L1, boosted anti-tumor activity. Preclinically, bezafibrate, a hyperlipidemia drug, upregulated CPT1A and synergized with CTLA-4 monoclonal antibody to inhibit tumor growth. Clinically, higher PD-L1 and lower CPT1A levels in tumors correlated with better anti-PD-1 therapy responses, suggesting potential biomarkers for prediction of treatment efficacy.

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