Cell Reports (Jun 2024)
Blockage of L2HGDH-mediated S-2HG catabolism orchestrates macrophage polarization to elicit antitumor immunity
- Shuang Feng,
- Duowei Wang,
- Yanyan Jin,
- Shi Huang,
- Tong Liang,
- Wei Sun,
- Xiuli Du,
- Luoyi Zhuo,
- Chun Shan,
- Wenbo Zhang,
- Tian Jing,
- Sen Zhao,
- Ruisi Hong,
- Linjun You,
- Guilai Liu,
- Leilei Chen,
- Dan Ye,
- Xianjing Li,
- Yong Yang
Affiliations
- Shuang Feng
- Institute of Translational Medicine, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China; School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China; Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China
- Duowei Wang
- Institute of Translational Medicine, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China; School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China; Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China
- Yanyan Jin
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China; Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China
- Shi Huang
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China; Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China
- Tong Liang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China; Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China
- Wei Sun
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China; Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China
- Xiuli Du
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China; Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China
- Luoyi Zhuo
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China; Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China
- Chun Shan
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China; Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China
- Wenbo Zhang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China; Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China
- Tian Jing
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China
- Sen Zhao
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China; Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China
- Ruisi Hong
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China; Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China
- Linjun You
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China; Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China
- Guilai Liu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China; Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China
- Leilei Chen
- Institutes of Biomedical Science, Shanghai Medical College, Fudan University, Shanghai, P.R. China
- Dan Ye
- Institutes of Biomedical Science, Shanghai Medical College, Fudan University, Shanghai, P.R. China; Corresponding author
- Xianjing Li
- Institute of Translational Medicine, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China; School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China; Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China; Corresponding author
- Yong Yang
- Institute of Translational Medicine, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China; School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China; Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China; School of Pharmacy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, P.R. China; Corresponding author
- Journal volume & issue
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Vol. 43,
no. 6
p. 114300
Abstract
Summary: The high infiltration of tumor-associated macrophages (TAMs) in the immunosuppressive tumor microenvironment prominently attenuates the efficacy of immune checkpoint blockade (ICB) therapies, yet the underlying mechanisms are not fully understood. Here, we investigate the metabolic profile of TAMs and identify S-2-hydroxyglutarate (S-2HG) as a potential immunometabolite that shapes macrophages into an antitumoral phenotype. Blockage of L-2-hydroxyglutarate dehydrogenase (L2HGDH)-mediated S-2HG catabolism in macrophages promotes tumor regression. Mechanistically, based on its structural similarity to α-ketoglutarate (α-KG), S-2HG has the potential to block the enzymatic activity of 2-oxoglutarate-dependent dioxygenases (2-OGDDs), consequently reshaping chromatin accessibility. Moreover, S-2HG-treated macrophages enhance CD8+ T cell-mediated antitumor activity and sensitivity to anti-PD-1 therapy. Overall, our study uncovers the role of blockage of L2HGDH-mediated S-2HG catabolism in orchestrating macrophage antitumoral polarization and, further, provides the potential of repolarizing macrophages by S-2HG to overcome resistance to anti-PD-1 therapy.
