Table 1.

Working mechanisms of metabolites involved in adaptation to intratumoral metabolic stress, maintaining stemness and immune evasion

	Working enzymes in cancer	Metabolites	Working mechanism	References
Adaptation to intratumoral metabolic stress	Pyruvate kinase isozymes M2, PKM2	Decrease in downstream glycolytic products	Decreased carbon flux into TCA cycle	Christofk et al., 2008
	Serine hydroxymethyltransferase, SHMT2 (Serine→Glycine)	Excessive Glycine and NADPH	Limiting PKM2 activity and thus oxygen consumption decrease Redox control via production of NADPH	Fan et al., 2014; Kim et al., 2015a; Ye et al., 2014
	Carbonic anhydrase 9, CA9 (CO2, H2O→Bicarbonate, H+)	Excessive Bicarbonate	Binding with hydrogen forming H2CO3	Parks et al., 2011
Immune evasion	Lactate dehydrogenase A, LDHA (Glucose→Lactate)	Limited glucose	Limit utility of glucose by T cells→ limiting for immune response	Fox et al., 2005
		Excessive lactate	Disturbing T cell metabolism and function by inhibition of lactic acid export of T cells	Fischer et al., 2007
			Suppression of T and NK cell activation	Brand et al., 2016; Fischer et al., 2007
			Inhibition of monocyte migration and cytokine release	Goetze et al., 2011
			Inhibition of dendritic cell activation	Gottfried et al., 2006
			Inhibition of TAM survival	Carmona-Fontaine et al., 2013
			Polarization of TAM to a M2 state, (M2 state TAM has a role in immunosuppression)	Colegio et al., 2014
	Indoleamine2,3-Dioxygenase1/Tryptophan 2,3-dioxygenase2, IDO1/TDO2 (Tryptophan→Kynurenine)	Limited tryptophan	Limit utility of tryptophan by T cells → amino acid deprivation-associated apoptosis of effector T cells	Fallarino et al., 2002
		Excessive kynurenine	Cell cycle arrest and apoptosis of T-cell by kynurenine	Fallarino et al., 2003
			Kynurenine acting as a ligand for aryl hydrocarbon receptor	Pilotte et al., 2012
	Ecto-5′-nucleotidases/Ectonucleoside triphosphate diphosphohydrolase1, CD39/CD73 (Nucleotide→Adenosine)	Excessive adenosine	Inhibition of T cell response and NK cell cytotoxicity	Hasko et al., 2008; Hausler et al., 2011
			Suppression of dendritic cell maturation and its pro-inflammatory cytokines production	Ryzhov et al., 2011
			Activation of immunosuppressive functions of MDSCs	Ryzhov et al., 2011
			Inhibition of phagocytic activity and nitric oxide and superoxide production in macrophage	Eppell et al., 1989; Hasko et al., 1996
			Inhibition of neutrophil degranulation	Bouma et al., 1997
Maintaining Stemness	gain-of-function mutation in isocitrate dehydrogenase1/2, IDH1/2 (αKG→D-2HG)	Excessive D-2HG	Suppression of gene involved in cell differentiation	Losman et al., 2013; Lu et al., 2012
	Lactate dehydrogenase A, Malate dehydrogenase, LDHA MDH1/2 (αKG→L-2HG)	Excessive L-2HG
	Loss-of-function mutation in succinate dehydrogenase, SDH (Succinate→Fumarate)	Excessive succinate	Silencing of crucial genes implicated in cell differentiation and EMT	Letouze et al., 2013
			Activation of a HIF response by the allosteric suppression of PHDs	Isaacs et al., 2005; Selak et al., 2005
	Loss-of-function mutation in fumarate hydratase, FH (Fumarate→Malate)	Excessive fumarate	Suppression of EMT-related genes	Sciacovelli et al., 2016
			Activation of a HIF response by the allosteric suppression of PHDs	Isaacs et al., 2005; Selak et al., 2005
	Dihydropyrimidine dehydrogenase (5FU→FU-H2)	Excessive dihydropyrimidine	EMT activation	Shaul et al., 2014
	Unknown	Excessive dendrogenin	A Activation of cancer cell differentiation	de Medina et al., 2013