Journal of Shanghai Jiao Tong University (Medical Science) >

2025 , Vol. 45 >Issue 9: 1239 - 1248

DOI: https://doi.org/10.3969/j.issn.1674-8115.2025.09.016

Review

Role of isocitrate dehydrogenase 1 mutation-mediated D-2-hydroxyglutarate metabolic reprogramming in tumor immunoregulation and progress in related drug development

  • YANG Quanjun ,
  • BAI Dingyuan ,
  • ZHOU Yuxuan ,
  • BAI Lu ,
  • GUO Cheng
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  • Department of Pharmacy, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
YANG Quanjun, E-mail: myotime@sjtu.edu.cn.

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)

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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.

Key words： isocitrate dehydrogenase 1 (IDH1); D-2-hydroxyglutarate (D2HG); immunoregulation; ivosidenib; vorasidenib; metabolic reprogramming

Cite this article

YANG Quanjun , BAI Dingyuan , ZHOU Yuxuan , BAI Lu , GUO Cheng . Role of isocitrate dehydrogenase 1 mutation-mediated D-2-hydroxyglutarate metabolic reprogramming in tumor immunoregulation and progress in related drug development[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025 , 45(9) : 1239 -1248 . DOI: 10.3969/j.issn.1674-8115.2025.09.016

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