Alterations in PD-L1 succinylation shape anti-tumor immune responses in melanoma
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.
Authors
- Lin Zhu (ORCID: https://orcid.org/0000-0001-5772-9482)
- Lan Gong (ORCID: https://orcid.org/0000-0003-3136-1565)
- Shuang Zhao (ORCID: https://orcid.org/0000-0001-7081-6177)
- Tao Ding (ORCID: https://orcid.org/0000-0002-7354-0994)
- Fanglin Zhang (ORCID: https://orcid.org/0000-0003-2039-509X)
- Poyee Lau
- Xinwei Kuang (ORCID: https://orcid.org/0000-0003-0665-6038)
- Mien‐Chie Hung (ORCID: https://orcid.org/0000-0003-4317-4740)
- Dingan Luo (ORCID: https://orcid.org/0000-0003-0933-2960)
- Dandan Liu
- Xin Li (ORCID: https://orcid.org/0000-0001-9024-7522)
- Jing Liu (ORCID: https://orcid.org/0000-0001-5588-3865)
- Bin Hu (ORCID: https://orcid.org/0000-0002-2974-1166)
- Hong Liu (ORCID: https://orcid.org/0000-0001-9976-2985)
- Hui Li (ORCID: https://orcid.org/0000-0003-4759-1779)
- Xiang Chen (ORCID: https://orcid.org/0000-0001-8187-636X)
- Juan Su (ORCID: https://orcid.org/0000-0001-7035-2560)
- Xiaowei Liang (ORCID: https://orcid.org/0000-0001-6983-428X)
- Long Liang (ORCID: https://orcid.org/0000-0002-2538-6726)
- Wenbin Zhou (ORCID: https://orcid.org/0000-0003-1855-0134)
- Yi He (ORCID: https://orcid.org/0000-0003-3939-0168)
- Zhuofeng Li
Institutions
- Central South University (CN)
- China Medical University (TW)
- SKiN Health (CA)
- Hunan Cancer Hospital (CN)
- Xiangya Hospital Central South University (CN)
- University College London (GB)
Publication Details
- Journal
- Nature Genetics
- Published
- 2025-03-01
- DOI
- https://doi.org/10.1038/s41588-025-02077-6
- Citations
- 58
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 46.25
Funders
- National Natural Science Foundation of China
- Key Programme