Immunometabolite L-2-HG promotes epigenetic modification of exhausted T cells and improves antitumor immunity
This study aimed to explore the potential correlation between the metabolic intermediate L-2-hydroxyglutarate (L-2-HG) and T cell exhaustion, as well as the underlying mechanisms involved. In this study, we investigated the presence of exhausted T (Tex) cells in patients under certain conditions: HIV infection, chronic leukemia, and hepatocellular carcinoma. To gain insights into the epigenetic signatures and transcriptome changes in Tex cells, we employed a combination of RNA-seq and ATAC-seq analyses. To evaluate the impact of L-2-HG on mitochondrial function, differentiation, and antitumor capacity of Tex cells, we utilized in vitro cell culture experiments and animal tumor models. We observed mitochondrial depolarization and metabolic dysfunction in Tex cells, accompanied by a significant reduction in L-2-HG levels. Moreover, altered epigenetic characteristics were observed in Tex cells, including a substantial increase in H3K27me3 abundance. Culturing Tex cells with L-2-HG demonstrated improved mitochondrial metabolism, reduced H3K27me3 abundance, and enhanced memory T cell differentiation. In a mouse melanoma tumor model, L-2-HG-treated CD8+ T cells for adoptive therapy led to significantly reduced tumor volume and significantly enhanced effector function of T cells. The study revealed that L-2-HG acted as an immune metabolite through epigenetic modifications of Tex cells.
Authors
- Yan Lü (ORCID: https://orcid.org/0000-0003-3468-2241)
- Mingyue Ma (ORCID: https://orcid.org/0000-0003-4440-1618)
- Cheng‐Chao Ruan (ORCID: https://orcid.org/0000-0001-5229-9428)
- Zhou‐Li Cheng (ORCID: https://orcid.org/0009-0002-1961-534X)
- Ying Yang (ORCID: https://orcid.org/0000-0002-8104-5985)
- Duojiao Wu (ORCID: https://orcid.org/0000-0003-2562-8825)
- Ying‐Hong Shi (ORCID: https://orcid.org/0000-0002-1833-8988)
- Xiangdong Wang (ORCID: https://orcid.org/0000-0002-0409-322X)
- Hua Wang (ORCID: https://orcid.org/0000-0002-2605-5697)
- Zheng Zhang (ORCID: https://orcid.org/0000-0002-3544-1389)
- Xiaoyan Li (ORCID: https://orcid.org/0000-0003-1006-7674)
- Xiaoyang Li (ORCID: https://orcid.org/0000-0003-4309-8709)
- Fangming Liu (ORCID: https://orcid.org/0000-0002-9601-4612)
- Yanying Yang
Institutions
- Sun Yat-sen University (CN)
- Shanghai Jiao Tong University (CN)
- Anhui Medical University (CN)
- Fudan University (CN)
- XinHua Hospital (CN)
- Ruijin Hospital (CN)
- Southern University of Science and Technology (CN)
- Wuhan University (CN)
- Jinshan Hospital of Fudan University (CN)
- Zhongnan Hospital of Wuhan University (CN)
- Zhongshan Hospital (CN)
- The First Affiliated Hospital, Sun Yat-sen University (CN)
- First Affiliated Hospital of Anhui Medical University (CN)
- Shanghai Sixth People's Hospital (CN)
- Shanghai Institute of Hematology (CN)
- Shenzhen Third People’s Hospital (CN)
- State Key Laboratory of Medical Neurobiology
- University of Science and Technology Beijing (CN)
Publication Details
- Journal
- JCI Insight
- Published
- 2025-03-04
- DOI
- https://doi.org/10.1172/jci.insight.174600
- Citations
- 7
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 6.55
Funders
- National Natural Science Foundation of China