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

doi:10.3969/j.issn.1674-8115.2025.09.016

Abstract

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

CLC Number:

R967

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.

Figures/Tables 3

TrendMD

References 77

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Cancer	Incidence	Key mechanism of action	Clinical feature	Reference
Glioma	60%‒80% (low level); 5%‒10% (glioblastoma)	D-2HG inhibits α-KG-dependent dioxygenase, leading to a G-CIMP phenotype; causes epigenetic dysregulation and inhibition of cellular differentiation; reduces CD8⁺ T cell infiltration	Better prognosis (vs. IDH wild type)	[39-41]
AML	10%‒15%	D-2HG inhibits normal hematopoietic progenitor cell differentiation; mutant IDH1/2 maintains NADPH homeostasis; upregulates PD-L1 expression and suppresses T-cell function	Longer median survival (vs. IDH wild type); susceptible to combined NPM1/FLT3 mutations	[42-44]
Cholangiocarcinoma	10%‒15% (intrahepatic)	D2HG accumulation leads to mitochondrial dysfunction; epigenetic silencing inhibits tumor suppressor gene expression; activation of HIF-1α pathway promotes tumor angiogenesis	Mutually exclusive with FGFR2 fusion; poorer prognosis	[45-46]
Chondrosarcoma	40%‒50%	Inhibits chondrocyte maturation; promotes abnormal cartilage matrix secretion; increases invasiveness	Low-grade tumors predominate; resistant to conventional chemotherapy	[47-48]
MDS	<5%	D2HG inhibits hematopoietic stem cell differentiation; epigenetic abnormalities lead to genomic instability	IDH mutation with TP53 mutation, very poor prognosis	[49-50]
Prostate cancer	<5%	Abnormal androgen signaling through epigenetic regulation of the AR pathway; metabolic synergy	Co-mutated with PTEN deletion; sensitive to PARP inhibitors	[51-52]
Colorectal cancer	<5%	Rare mutations, often associated with microsatellite stabilization (MSS) or KRAS wild-type isoforms	Prognosis not significantly different from wild type; some patients stabilized, but limited efficacy	[37, 53]
Thyroid cancer	<5%	Metabolic reprogramming affects oxidative stress; synergistic progression with BRAF co-mutations	Poor prognosis; limited sample size; mechanism of resistance not defined	[38, 54]

Cancer	Incidence	Key mechanism of action	Clinical feature	Reference
Glioma	60%‒80% (low level); 5%‒10% (glioblastoma)	D-2HG inhibits α-KG-dependent dioxygenase, leading to a G-CIMP phenotype; causes epigenetic dysregulation and inhibition of cellular differentiation; reduces CD8⁺ T cell infiltration	Better prognosis (vs. IDH wild type)	[39-41]
AML	10%‒15%	D-2HG inhibits normal hematopoietic progenitor cell differentiation; mutant IDH1/2 maintains NADPH homeostasis; upregulates PD-L1 expression and suppresses T-cell function	Longer median survival (vs. IDH wild type); susceptible to combined NPM1/FLT3 mutations	[42-44]
Cholangiocarcinoma	10%‒15% (intrahepatic)	D2HG accumulation leads to mitochondrial dysfunction; epigenetic silencing inhibits tumor suppressor gene expression; activation of HIF-1α pathway promotes tumor angiogenesis	Mutually exclusive with FGFR2 fusion; poorer prognosis	[45-46]
Chondrosarcoma	40%‒50%	Inhibits chondrocyte maturation; promotes abnormal cartilage matrix secretion; increases invasiveness	Low-grade tumors predominate; resistant to conventional chemotherapy	[47-48]
MDS	<5%	D2HG inhibits hematopoietic stem cell differentiation; epigenetic abnormalities lead to genomic instability	IDH mutation with TP53 mutation, very poor prognosis	[49-50]
Prostate cancer	<5%	Abnormal androgen signaling through epigenetic regulation of the AR pathway; metabolic synergy	Co-mutated with PTEN deletion; sensitive to PARP inhibitors	[51-52]
Colorectal cancer	<5%	Rare mutations, often associated with microsatellite stabilization (MSS) or KRAS wild-type isoforms	Prognosis not significantly different from wild type; some patients stabilized, but limited efficacy	[37, 53]
Thyroid cancer	<5%	Metabolic reprogramming affects oxidative stress; synergistic progression with BRAF co-mutations	Poor prognosis; limited sample size; mechanism of resistance not defined	[38, 54]

Inhibitor	Phase	Cancer type	Key result	Reference
Ivosidenib (AG-120)	Available	Relapsed/refractory AML; cholangiocarcinoma	In a Phase Ⅲ trial in cholangiocarcinoma: median OS = 10.3 months; 51% reduction in risk of death. In AML (Phase Ⅲ): median OS = 24 months in combination with azacitidine	[42, 64]
Vorasidenib (AG-881)	Available	IDH1/2 mutant glioma	In double-blind Phase Ⅲ trial: median PFS 27.7 months vs 11.1 months (placebo)	[23]
Olutasidenib (FT-2102)	Available	Relapsed/refractory AML	ORR 46%, median OS 10.5 months, CR/CRh 35%. Combination with azacitidine: CR/CRh 45% (treatment-naïve) vs 30% (previously treated)	[65-67]
DS-1001 (AB-218)	Ⅰ	Glioma, AML, cholangiocarcinoma	Non-enhancing glioma ORR 33%, enhancing ORR 17.1%	[68]
AGI-5198	Preclinical	Glioma	Inhibits mutant IDH1 enzyme; reduces D-2HG production; restores histone H3K9me3 demethylation and differentiation marker expression (GFAP)	[69]
ML309	Preclinical	IDH1 mutant glioma, colon cancer	Reduced D-2HG in glioma; reversed DNA hypermethylation and gene silencing in colon cancer (with vitamin C)	[70-71]
Ranosidenib (HMPL-306)	Ⅰ/Ⅱ	AML, IDH1/2 mutant hematologic and solid tumors	Inhibition of mutant IDH1/2; reduced D-2HG; in AML Phase Ⅰ: CR/CRh 42%; remission in 67% (treatment-naïve) vs 29% (pretreated)	[63, 72]
IHMT-IDH1-053	Preclinical	IDH1 mutated solid tumors and hematological tumors	Covalently binds to Cys269; selectively inhibits mutant enzyme (IC₅₀=4.7 nmol·L^-1); reduces D-2HG (IC₅₀=28 nmol·L^-1 in transfected cells)	[62]
BAY1436032	Ⅰ	IDH1 mutant cholangiocarcinoma, AML	ORR 25%; PFS 5.6 months; median OS 12.8 months. In AML Phase Ⅰ: ORR 15%, 30% stable disease	[73-74]
LY3410738	Ⅰ	IDH1 mutant cholangiocarcinoma and other solid tumors, AML	Broad-spectrum inhibition of IDH1 R132H/C/G/S/L; manageable safety profile. In AML: in combination with cytarabine/doxorubicin, tumor inhibition 82%, median OS extended to 32 d	[75-76]
IDH305	Ⅰ	AML, MDS	CR/CRh/PR 35% (42% in AML, 28% in MDS); remission rate 57% in treatment-naïve vs 29% in pretreated	[77]

Inhibitor	Phase	Cancer type	Key result	Reference
Ivosidenib (AG-120)	Available	Relapsed/refractory AML; cholangiocarcinoma	In a Phase Ⅲ trial in cholangiocarcinoma: median OS = 10.3 months; 51% reduction in risk of death. In AML (Phase Ⅲ): median OS = 24 months in combination with azacitidine	[42, 64]
Vorasidenib (AG-881)	Available	IDH1/2 mutant glioma	In double-blind Phase Ⅲ trial: median PFS 27.7 months vs 11.1 months (placebo)	[23]
Olutasidenib (FT-2102)	Available	Relapsed/refractory AML	ORR 46%, median OS 10.5 months, CR/CRh 35%. Combination with azacitidine: CR/CRh 45% (treatment-naïve) vs 30% (previously treated)	[65-67]
DS-1001 (AB-218)	Ⅰ	Glioma, AML, cholangiocarcinoma	Non-enhancing glioma ORR 33%, enhancing ORR 17.1%	[68]
AGI-5198	Preclinical	Glioma	Inhibits mutant IDH1 enzyme; reduces D-2HG production; restores histone H3K9me3 demethylation and differentiation marker expression (GFAP)	[69]
ML309	Preclinical	IDH1 mutant glioma, colon cancer	Reduced D-2HG in glioma; reversed DNA hypermethylation and gene silencing in colon cancer (with vitamin C)	[70-71]
Ranosidenib (HMPL-306)	Ⅰ/Ⅱ	AML, IDH1/2 mutant hematologic and solid tumors	Inhibition of mutant IDH1/2; reduced D-2HG; in AML Phase Ⅰ: CR/CRh 42%; remission in 67% (treatment-naïve) vs 29% (pretreated)	[63, 72]
IHMT-IDH1-053	Preclinical	IDH1 mutated solid tumors and hematological tumors	Covalently binds to Cys269; selectively inhibits mutant enzyme (IC₅₀=4.7 nmol·L^-1); reduces D-2HG (IC₅₀=28 nmol·L^-1 in transfected cells)	[62]
BAY1436032	Ⅰ	IDH1 mutant cholangiocarcinoma, AML	ORR 25%; PFS 5.6 months; median OS 12.8 months. In AML Phase Ⅰ: ORR 15%, 30% stable disease	[73-74]
LY3410738	Ⅰ	IDH1 mutant cholangiocarcinoma and other solid tumors, AML	Broad-spectrum inhibition of IDH1 R132H/C/G/S/L; manageable safety profile. In AML: in combination with cytarabine/doxorubicin, tumor inhibition 82%, median OS extended to 32 d	[75-76]
IDH305	Ⅰ	AML, MDS	CR/CRh/PR 35% (42% in AML, 28% in MDS); remission rate 57% in treatment-naïve vs 29% in pretreated	[77]