Role of isocitrate dehydrogenase 1 mutation-mediated D-2-hydroxyglutarate metabolic reprogramming in tumor immunoregulation and progress in related drug development
10.3969/j.issn.1674-8115.2025.09.016
- VernacularTitle: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
- Author:
Quanjun YANG
1
;
Dingyuan BAI
1
;
Yuxuan ZHOU
1
;
Lu BAI
1
;
Cheng GUO
1
Author Information
1. 上海交通大学医学院附属第六人民医院药剂科,上海 200233
- Publication Type:Journal Article
- Keywords:
isocitrate dehydrogenase 1(IDH1);
D-2-hydroxyglutarate(D2HG);
immunoregulation;
ivosidenib;
vorasidenib;
metabolic reprogramming
- From:
Journal of Shanghai Jiaotong University(Medical Science)
2025;45(9):1239-1248
- CountryChina
- Language:Chinese
-
Abstract:
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.
