Cancer immunometabolism: advent, challenges, and perspective

Dang, Qin; Li, Borui; Jin, Bing; Ye, Zeng; Lou, Xin; Wang, Ting; Wang, Yan; Pan, Xuan; Hu, Qiangsheng; Li, Zheng; Ji, Shunrong; Zhou, Chenjie; Yu, Xianjun; Qin, Yi; Xu, Xiaowu

doi:10.1186/s12943-024-01981-5

Molecular Cancer

Table 1 Evolving roles alters the immunometabolism of cancer cell survival and growth

From: Cancer immunometabolism: advent, challenges, and perspective

Metabolites	Target immune cell	Mediators	Effects on immunity	Outcomes	Refer to Refs.
Glu	T_reg cell	mGlutR1	Enhancement of T_reg proliferation, activation, and immunosuppression	Pro-cancer	[9]
FA	T_reg cell	SREBP and FASN	SREBP combined with FASN promotes FA synthesis, which in turn promotes T_reg maturation and drives immunosuppression	Pro-cancer	[11]
	T_reg cell	SREBP and FASN	Inhibition of FASN reduces fat accumulation in hepatocytes and directly suppresses immune cells and stellate cells	Anti-cancer	[122]
	CD8⁺ T cell	STAT3	The leptin-STAT3 axis increases oxidation of FAs within CD8⁺ T cells in breast cancer	Pro-cancer	[81]
	CD8⁺ T cell	CD36	CD36 mediated uptake of FA by CD8⁺ T cells, induced lipid peroxidation and ferroptosis, and led to reduced cytotoxic cytokine production	Pro-cancer	[161]
	B cell	CD37	As essential membrane-localized inhibitor of FA metabolism, CD37 inhibits FATP1 (FA transporter) and subsequently leads to the inhibition of FA metabolism in aggressive B cell lymphomas	Anti-cancer	[162]
isoDCA	DCs and T_reg cell	NR1H4; Foxp3	isoDCA inhibits the transcriptional activity of NR1H4 in DCs and attenuate the immunostimulatory properties of DCs, which in turn induces Foxp3 expression and T_reg cell generation	Anti-cancer	[16]
Cholesterol	Neutrophil and CD8⁺ T cell	CXCR2	Depletion of toxic γδ-T cells promotes breast cancer metastasis	Pro-cancer	[23]
	Tc9 cell	LXR	Cholesterol or its derivative oxysterols inhibited IL-9 expression by activating LXR Sumoylation-NF-κB signaling	Pro-cancer	[163]
	Neutrophil	CXCR2	Recruiting neutrophils to achieve a state of local TME inhibition	Pro-cancer	[164]
	Neutrophil	HIF1α	Promoting angiogenesis in pancreatic neuroendocrine tumors	Pro-cancer	[165]
Leu	B cell	LARS2	LARS2 knockdown or leucine blockade reduces LARS2-expressing B-cell subpopulations, which in turn inhibits immune escape in colorectal cancer	Anti-cancer	[44]
Arg	CD8⁺ T cell	ARG1	Extracellular ARG1could interact with cathepsin S and enhanced enzymatic activity at physiological pH, and NET-associated hARG1 suppresses T lymphocytes	Pro-cancer	[166]
PGE2	NK cell and cDC1	may be XCL1 and CCL5	Direct inhibition of NK cell survival and chemokine production that followed by downregulation of chemokine expression in cDC1	Pro-cancer	[96]
Lactate	T_reg cell	MCT1	Upregulation of lactate metabolic pathways to maintain immune response	Anti-cancer	[98]
Lactate	Cytotoxic T cell	SUCNR1	Lactate reduces PC activity, succinate secretion and SUCNR1 activation, which inhibits autocrine signaling in cytotoxic T cells	Pro-cancer	[102]
αKG	Macrophage	Jmjd3; NF-κB	Coordinates M2 type activation of macrophages; Impairment of the pro-inflammatory response of M1 macrophages	Pro-cancer	[95]
Glycerol	Memory CD8⁺ T cells	IL-7	IL-7 signaling induces glycerol uptake to promote triacylglycerol synthesis and FAO, thus supporting the longevity of memory CD8⁺ T cells	Anti-cancer	[167]
Trp	CD8⁺ T cell	I3A	L. reuteri promotes interferon-gamma-producing CD8⁺ T cells that thereby enhancing immune checkpoint inhibitor therapy	Anti-cancer	[60]
Asn	CD8⁺ T cell	NRF2	Asn restriction enhances the metabolic capacity and anti-tumor function of CD8⁺ T cells	Anti-cancer	[66]

CXCR2 C-X-C motif chemokine receptor 2, FA Fatty acid, PGE2 Prostaglandin E2, HIF1α Hypoxia-inducible factor-1α, isoDCA 3β-hydroxydeoxycholic acid, DCs Dendritic cells, TME Tumor microenvironment, TANs Tumor-associated neutrophils, NK cell Natural killer cell, cDC1 Conventional type 1 dendritic cell, Tc9 cell IL-9-secreting CD8⁺ T cell, LXR Liver X receptor, Arg Arginine, ARG1 Arginase 1, NETs Neutrophil extracellular traps, hARG1 Human arginase 1, PC Pyruvate carboxylase, αKG α-ketoglutarate, NF-κB Nuclear factor-κB, I3A Indole-3-aldehyde, IFN-γ Interferon-gamma, Trp Tryptophan, Asn Asparagine, Glu Glutamate, T_reg cell Regulatory T cell, mGlutR1 Metabotropic glutamate receptor 1, Leu Leucine, LARS2 Leucine-tRNA-synthase-2

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