ArticleJCI insight2025
Immunometabolite L-2-HG promotes epigenetic modification of exhausted T cells and improves antitumor immunity.
Article in JCI insight, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- The Cancer Cell Metabolic Reprogramming Remodels the Tumor Microenvironment: Molecular Mechanisms and Therapeutic Strategies.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Mitochondrial metabolism and PD-1 blockade: mechanisms and therapeutic opportunities in cancer immunotherapy.Molecular biology reports · 2026Review
- L-2-Hydroxyglutarate sensitizes ferroptosis through ATF3/CHAC1-mediated glutathione degradation in hepatocellular carcinoma.Cell death & disease · 2026Article
- T Cell Exhaustion in Cancer Immunotherapy: Heterogeneity, Mechanisms, and Therapeutic Opportunities.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Single-cell profiling reveals immunometabolic remodeling with T-cell dysfunction in HIV-1 infected people.Infectious diseases & immunity · 2026Article
- Immune Exhaustion in Chronic Infection and Cancer: Signaling Pathways and Therapeutic Interventions.MedComm · 2026Review
- Supercharging the metabolic engine: mitochondrial engineering strategies for CAR-T persistence in solid tumors.Frontiers in immunology · 2026Review
- The embedding of stress: mitophagy as a mechanism for the central nervous system (CNS) programming and lifelong disease vulnerability.Frontiers in cell and developmental biology · 2026Review
- Post-translational modifications in CD8Frontiers in immunology · 2026Review
- Immunometabolism: crosstalk with tumor metabolism and implications for cancer immunotherapy.Molecular cancer · 2025Review
- Mitochondrial Transfer Between Cancer and T Cells: Implications for Immune Evasion.Antioxidants (Basel, Switzerland) · 2025Review
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Authors and funding
14 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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