TABLE 3.

The effect of oncometabolites on epigenetic dysfunction and immunosuppression.

Oncometabolite	Metabolic enzymes	Epigenetic dysfunction	Immunosuppressive effect	Malignancies	References
D-2-hydroxyglutarate	IDH1/2	DNA and histone hypermethylation	NA	Glioblastoma multiforme, ALL, Chondrosarcoma, Cholangiocarcinoma	Dang et al. (2009); Amary et al. (2011); Borger et al. (2014); Shim et al. (2014); Waterfall et al. (2014); Colvin et al. (2016)
L-2-hydroxyglutarate	L2HGDH	DNA and histone hypermethylation	NA	Brain tumors, Renal cell carcinoma	Aghili et al. (2009); Rogers et al. (2010)
Succinate	SDH	DNA and histone hypermethylation	TAM marker gene expression ↑	Pheochromocytomas, Paragangliomas	Hao et al. (2009); Bardella et al. (2011); Zhang et al. (2011); Yang et al. (2013); Williamson et al. (2015); Jiang and Yan, (2017); Mu et al. (2017)
			IL-6 secretion ↑
Fumarate	FH	DNA and histone hypermethylation	Neutrophils, T-cell, B-cell response ↓	Pheochromocytomas, Paragangliomas	Kinch et al. (2011); Fieuw et al. (2012); Sullivan et al. (2013); Zheng et al. (2013b); Castro-Vega et al. (2014); Shanmugasundaram et al. (2014); Yang et al. (2014); Jin et al. (2015); Zheng et al. (2015)
			Inhibiting DC maturation
			CD150, CD40, CD86 expression ↓
			CTLA-4, PD-L1 expression ↑
			IL-6, IL-1β, TNF-α secretion ↓
Lactate	MCT/LDH	Histone acetylation	PD-1, PD-L1, CTLA-4 expression ↑	Lung carcinoma, Melanoma, Prostate cancer	(Colegio et al., 2014; El-Kenawi et al., 2019)
			Inhibiting the differentiation of monocytes to DCs
			Inhibiting the differentiation of progenitor cells to CD4+ and CD8+ T-cell

IDH1/2, isocitrate dehydrogenase; L2HGDH, L-2-hydroxyglutarate dehydrogenase; SDH, succinate dehydrogenase; FH, fumarate hydratase; MCT, monocarboxylate transporter; LDH, lactate dehydrogenase; TAM, tumor-associated macrophages; ALL, acute lymphoblastic leukemia; NA, not applicable.