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Since the discovery of gain-of-function mutations in the tricarboxylic acid (TCA) cycle enzyme isocitrate dehydrogenase (IDH) and the resulting accumulation of the metabolite d-2-hydroxyglutarate (d-2HG) in several tumor entities (such as glioma, acute myeloid leukemia (AML), and cholangiocarcinoma) about 10 years ago research has focused on the tumor cell-intrinsic consequences. d-2HG acting as an oncometabolite was shown to promote proliferation, anoikis, tumorigenesis, and differentiation block of hematopoietic cells in an autocrine fashion. Although the prognostic value of the different types of IDH mutations remains controversial the development of inhibitors against mutated IDH is flourishing. On the other hand, serum levels of d-2HG proved to be a more robust adverse prognostic marker in AML and glioma. Surprisingly, until recently only few studies on the paracrine effects of this oncometabolite on the tumor microenvironment with particular focus on the innate or adaptive immunity were available. Now, three recent publications focused on the paracrine effects of tumor-derived d-2HG on T-cells in the context of AML and glioma. It was shown that T-cells are capable of efficiently taking up d-2HG in vitro, which was mirrored by 2HG-enriched T-cells exclusively found in samples from patients with IDH-mutated AML and glioma. Furthermore, all three studies describe an impairment of T-cell activation (although to different extents). The published effects could be at least partly attributed to metabolic alterations evoked by d-2HG influencing amongst others mTOR signaling, Hif-1α protein stability, the balance between aerobic glycolysis and oxidative phosphorylation, and the abundance of ATP (with according changes of AMPK activation). In the context of glioma it was further shown that IDH mutations and high d-2HG levels lead to reduced T-cell migration and consequently lowered T-cell infiltration at the tumor site. Moreover, two of the studies showed an increased frequency of FoxP3+ Tregs. Nevertheless, effects on downstream mechanisms and consequences have been differently addressed in the independent studies, and taken together the findings shed more light on the potentially targetable sites for improving therapeutic approaches. While the work by our group demonstrated profound impairments of Th17 polarization resulting from d-2HG-triggered Hif-1α protein destabilization the comprehensive analyses by Bunse et al. highlighted an inhibitory effect of d-2HG on the intracellular calcium signaling (downstream of the T-cell receptor) and an activation of AMPK signaling with resulting NFAT inhibition leading to the aforementioned activation defects. The summarized results of all three studies emphasized the importance of d-2HG not only as an autocrine but also a paracrine oncometabolite capable of shaping the tumor microenvironment in several facets adding to the common concept of tumor immune escape mechanisms. Those findings could lead to further improvements of the current targeted treatment strategies applied to patients harboring IDH mutations especially in view of the increasing importance of (combined) immune-based therapeutic approaches.

Immunometabolic Regulation of Anti-Tumor T-Cell Responses by the Oncometabolite D-2-Hydroxyglutarate