Immunometabolite L-2-HG promotes epigenetic modification of exhausted T cells and improves antitumor immunity

作者：Yanying Yang, Xiaoyan Li, Fangming Liu, Mingyue Ma, Ying Yang, Cheng‐Chao Ruan, Yan Lü, Xiaoyang Li, Xiangdong Wang, Ying–Hong Shi, Zheng Zhang, Hua Wang, Zhou‐Li Cheng, Duojiao Wu · 发表于：JCI Insight · 年份：2025 · DOI：10.1172/jci.insight.174600 · 被引用次数：12 · 研究领域：Cancer, Hypoxia, and Metabolism、Immune cells in cancer、Cancer Research and Treatments

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.