收稿日期: 2025-04-24
录用日期: 2025-07-03
网络出版日期: 2025-09-30
基金资助
国家自然科学基金(82272925);上海交通大学医学院“双百人”项目(20240815)
Role of isocitrate dehydrogenase 1 mutation-mediated D-2-hydroxyglutarate metabolic reprogramming in tumor immunoregulation and progress in related drug development
Received date: 2025-04-24
Accepted date: 2025-07-03
Online published: 2025-09-30
Supported by
National Natural Science Foundation of China(82272925);“Two-hundred Talents” Program of Shanghai Jiao Tong University School of Medicine(20240815)
异柠檬酸脱氢酶1（isocitrate dehydrogenase 1，IDH1）突变可异常产生致癌代谢物D-2-羟基戊二酸（D-2-hydroxyglutarate，D2HG），进而重塑肿瘤免疫微环境，近年来已成为肿瘤代谢-免疫交互研究的关键靶点。D2HG通过竞争性抑制内源性α-酮戊二酸依赖性双加氧酶，引发DNA组蛋白过甲基化与细胞分化阻滞，从而促进肿瘤的发生、发展、转移，并促使肿瘤产生耐药性。同时，D2HG抑制T细胞功能，促进髓系细胞扩增以及巨噬细胞极化，削弱免疫监视能力，形成免疫抑制状态，对免疫治疗响应产生影响。在胶质瘤、急性髓系白血病、胆管癌等多种肿瘤中，IDH1呈现出异质性和不同的预后特征。目前，针对IDH1突变的小分子抑制剂，如艾伏尼布（ivosidenib）、沃拉西尼布（vorasidenib）等，能够通过降低D2HG水平，部分逆转免疫抑制，在临床试验中显示出一定的疗效。然而，这些抑制剂存在疗效差异、耐药性及安全性等问题。IDH1抑制剂联合治疗旨在协同逆转代谢-表观遗传-免疫三重抑制网络，增强抗肿瘤药理效应，因而受到广泛关注。该文综述了IDH1突变介导D2HG代谢的肿瘤免疫调控网络，并全面综述了相关药物研发进展，希冀为肿瘤防治提供参考和思路。
关键词： 异柠檬酸脱氢酶1（IDH1）; D-2-羟基戊二酸（D2HG）; 免疫调控; 艾伏尼布; 沃拉西尼布; 代谢重编程
杨全军 , 柏丁源 , 周雨萱 , 白露 , 郭澄 . 异柠檬酸脱氢酶1突变介导D-2-羟基戊二酸代谢重编程在肿瘤免疫调控中的作用及相关药物研发进展[J]. 上海交通大学学报（医学版）, 2025 , 45(9) : 1239 -1248 . DOI: 10.3969/j.issn.1674-8115.2025.09.016
Mutations in isocitrate dehydrogenase 1 (IDH1) can abnormally produce the oncometabolite D-2-hydroxyglutarate (D2HG), which in turn remodels the tumor immune microenvironment. In recent years, it has become a key target in the research on the interaction between tumor metabolism and immunity. D2HG competitively inhibits endogenous α-ketoglutarate-dependent dioxygenases, leading to DNA histone hypermethylation and cell differentiation arrest, thus promoting tumorigenesis, development, metastasis, and drug resistance. Meanwhile, D2HG suppresses T-cell function, promotes myeloid cell expansion and macrophage polarization, weakens immune surveillance, and creates an immunosuppressive state that affects the response to immunotherapy. In various tumors, such as glioma, acute myeloid leukemia, and cholangiocarcinoma, IDH1 mutations exhibit heterogeneity and different prognostic characteristics. Currently, small-molecule inhibitors targeting IDH1 mutations, such as ivosidenib and vorasidenib, can partially reverse immunosuppression by reducing D2HG levels and have shown certain efficacy in clinical trials. However, these inhibitors face challenges including efficacy differences, drug resistance, and safety concerns. Combination therapies with IDH1 inhibitors aim to synergistically reverse the metabolic-epigenetic-immune triple-suppression network and enhance the anti-tumor effects, attracting extensive attention. This article reviews the tumor immune regulatory network mediated by IDH1-mutation-induced D2HG metabolism and comprehensively summarizes progress in related drug development, providing new references and ideas for tumor prevention and treatment.
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