Oncometabolite 2-hydroxyglutarate regulates anti-tumor immunity

Abstract

"Oncometabolite" 2-hydroxyglutarate (2-HG) is an aberrant metabolite found in tumor cells, exerting a pivotal influence on tumor progression. Recent studies have unveiled its impact on the proliferation, activation, and differentiation of anti-tumor T cells. Moreover, 2-HG regulates the function of innate immune components, including macrophages, dendritic cells, natural killer cells, and the complement system. Elevated levels of 2-HG hinder α-KG-dependent dioxygenases (α-KGDDs), contributing to tumorigenesis by disrupting epigenetic regulation, genome integrity, hypoxia-inducible factors (HIF) signaling, and cellular metabolism. The chiral molecular structure of 2-HG produces two enantiomers: D-2-HG and L-2-HG, each with distinct origins and biological functions. Efforts to inhibit D-2-HG and leverage the potential of L-2-HG have demonstrated efficacy in cancer immunotherapy. This review delves into the metabolism, biological functions, and impacts on the tumor immune microenvironment (TIME) of 2-HG, providing a comprehensive exploration of the intricate relationship between 2-HG and antitumor immunity. Additionally, we examine the potential clinical applications of targeted therapy for 2-HG, highlighting recent breakthroughs as well as the existing challenges.

Keywords: 2-Hydroxyglutarate; Isocitrate dehydrogenase; Oncometabolite; Therapeutic target; Tumor immune microenvironment.

Fig. 1

The metabolism of 2-HG in cancer cell. (A) The role of IDH in the TCA cycle under physiological conditions. (B) The generation of 2-HG under pathological conditions. Generally, 2-HG is transformed from its substrate α-KG. The heterogenous mutation of IDH1/2 represents the primary source of D(R)-2-HG. Additionally, PHGDH and HOT convert α-KG to D(R)-2-HG in a NADH-dependent manner. L(S)-2-HG is predominantly produced by LDHA and MDH under hypoxic conditions. Reversely, 2-HG is catabolized by 2HGDH to maintain a relatively low level. Abnormal accumulation of 2-HG promotes the tumor progression by inhibiting α-KGDDs, adapting to hypoxia and metabolism reprogramming. TCA: tricarboxylic acid; IDH: isocitrate dehydrogenase; NADP+: nicotinamide adenine dinucleotide phosphate; α-KG: α-ketoglutarate; 2-HG: 2-hydroxyglutarate; MDH: malate dehydrogenase; LDHA: lactate dehydrogenase A; 2HGDH: 2-HG dehydrogenase; HOT: hydroxyacid-oxoacid transhydrogenase; FAD: flavin adenine dinucleotide.

Fig. 2

The impact of 2-HG on the adaptive immune system within TIME. D-2-HG generally contributes to the "cold tumor" characteristic by interfering with the proliferation and differentiation of CD8⁺ T cells. This interference occurs through the inhibition of Ca2+-dependent NFAT-mediated T cell activation, TET1/2-mediated DNA methylation, HIF-1α, LDHA, and the orchestration of glucose metabolism towards OXPHOS. Consequently, the cytotoxic effect and immune memory of CD8⁺ T cells are impaired. CD4⁺ T cells are also inhibited, resulting in a higher population of T_Reg cells and fewer effective cytokines released from mature CD4⁺ cells. In contrast, L-2-HG induces an immune-infiltrated status by upregulating the proliferation and differentiation of effector and memory T cells. 2-HG: 2-hydroxyglutarate; TIME: tumor immune microenvironment; TET: ten-eleven translocation; HIF: hypoxia-inducible factors; LDHA: lactate dehydrogenase A; OXPHOS: oxidative phosphorylation; T_Reg: regulatory T lymphocytes; STAT1: Signal transducer and activator of transcription 1.

Fig. 3

| Roles of 2-HG in modulating innate immune components. (A) LPS stimulation results in an increase of both D-2-HG and L-2-HG within macrophages. (B) Treatment with either D-2-HG or L-2-HG elicits a consistent response in LPS-activated DCs, characterized by diminished glycolysis, augmented OXPHOS, reduced secretion of the pro-inflammatory cytokine IL12, and downregulation of the dendritic cell maturation marker CD83. (C) Within tumor cells, D-2-HG recruits NK cells through CX3CL1- CX3CR1 interaction. Concurrently, D-2-HG leads to a diminution in the cytotoxic capabilities and a decrease in IFN-γ production in NK cells by constraining the expression of NKG2D receptor ligands ULBP1/3. In tumor-associated macrophages, D-2-HG activates TDO/L-kyn/AhR and suppresses the expression of pro-inflammatory molecules such as MHCII, CD86, and CD80, while simultaneously upregulating the secretion of the anti-inflammatory cytokine IL10. D-2-HG induces a tolerogenic phenotype in DCs. It upregulates the expression of immunosuppressive mediators such as PD-L1 and CD206 and reduces the expression of IL-6 and MHCII. Additionally, D-2-HG adversely impacts the complement system, characterized by less MAC formation and C3b deposition on tumor cell surfaces. Impaired the functions of macrophages and DCs indirectly inhibits T cell activity by. AhR, aryl hydrocarbon receptor; CR, complement receptor; CX3CL1, C-X3-C motif chemokine ligand 1; CX3CR1, C-X3-C motif chemokine receptor 1; D-2-HG, D-2-hydroxyglutarate; DC, dendritic cell; HIF1α, hypoxia-inducible factor 1-alpha; IFN-γ, interferon-gamma; IL-1β, interleukin-1 beta; IL-6, interleukin-6; IL-10; interleukin-10; IL-12, interleukin-12; iNOS, inducible nitric oxide synthase; L-kyn, l-kynurenine; L-trp, l-tryptophan; LAT1, L-type amino acid transporter 1; LPS, Lipopolysaccharide; MAC, membrane attack complex; MHCII, major histocompatibility complex class II; F-κB, nuclear factor kappa B; NK, natural killer; NKG2D, natural killer group 2D; NO, nitric oxide; OXPHOS, oxidative phosphorylation; PD-1, programmed death-1; PD-L1, programmed death-ligand 1; PHD, prolyl hydroxylase; SLC13A3, solute carrier family 13 member 3; TDO, tryptophan 2,3-dioxygenase; TET, ten-eleven translocation; TNF-α, tumor necrosis factor-alpha; ULBP1/3, UL16-binding protein 1/3.