Table 1 Functions of lactate and lactylation in tumor immunity

From: Lactate and lactylation in cancer

Immune cell type	Mechanism	Regulated gene	Cancer type	Function	Ref
TIMs	non-histone modifications (METTL3 K281, K345)	JAK1	CRC	induce immunosuppression and tumor immune evasion	²⁸
macrophages	histone modifications (H3K18)	Arg1, Vegfa	Breast cancer	drive M2 macrophage polarization	²⁰
macrophages	lactate metabolism	Arg1	LLC	induce ACLY-dependent H3K9ac, thereby upregulating the expression of M2-like genes.	²⁸⁷
macrophages	lactate metabolism	Arg1, Vegfa	Melanoma, LLC	drive M2 macrophage polarization and promote tumor growth	²⁸³
macrophages	lactate metabolism	Gpr132, CD206	Breast cancer	drive M2 macrophage polarization through Gpr132, thereby enhancing lung metastasis and invasiveness	²⁰⁶
macrophages	lactate metabolism	ATP6V0d2, HIF-2α	LLC	promote HIF-2α induced tumor vascularization and growth	²⁸⁴
macrophages	lactate metabolism	ERK1/2, STAT3	Breast cancer	drive M2 macrophage polarization	²⁸⁶
macrophages	lactate metabolism	SREBP2	Breast cancer	Downregulation of LDHB skews TAMs to function as a lactate and sterol/oxysterol source for the proliferation	²⁸⁹
macrophages	lactate metabolism	IL-23	LUAD	promote inflammation and tumor development.	²⁸⁸
microglia	lactate metabolism	IGFBP6, ARG1, CD206, CD163	GBM	drive M2 microglia polarization	²⁹⁰
macrophages	histone modifications (H3K18)	RARγ	CRC	enhance tumorigenesis through prohibiting RAΡγ expression and inducing IL-6 production, which activated STAT3 in tumor cells	²⁹⁴
DCs	lactate metabolism	IFN-α, IFN-γ	LLC	Inhibit DCs from presenting antigens and activating CD8 + T cells, preventing them from initiating an immune response within tumors in vivo	²⁸¹
DCs	lactate metabolism	IFN-α	Breast cancer	weaken IFNα induction and reduce the recruitment Treg cells	²⁹⁷
DCs	lactate metabolism	CD1a, CD80, CD86, CD16	Urothelial carcinoma, melanoma, prostate carcinoma	block the differentiation of TADC and reduce their IL-12 secretion	²⁷⁸
DCs	lactate metabolism	SREBP2	Melanoma	transform conventional DCs into CD63+ mregDCs through homeostatic or tolerogenic maturation	²⁸⁰
Treg cells	lactate metabolism	PD-1	CRC, melamoma, NSCLC, gastric cancar, AML	promote PD-1 expression in Treg cells, whereas dampening PD-1 expression by effector T cells	^298,299
Treg cells	lactate metabolism	LDHA, SLC16A1	Melanoma, HNSCC	counteract the destabilizing impact of high-glucose conditions towards Treg cells, thus promoting their proliferation and immunosuppressive function	³⁰⁰
Treg cells	non-histone modifications (APOC2 K70)	APOC2	NSCLC	produce FFA, recruit Treg cells and elicit immunotherapy resistance	³⁰⁰
NK cells, CD8⁺ T cells	lactate metabolism	IFN-γ, granzyme B	Melanoma	down-regulated LDHA promotes inflitration and enhances the therapeutic effect of anti-PD-1 therapy	³⁰²
CTL	lactate metabolism	JNK, c-Jun, p38	RCC	suppress CTL n a manner of immediate onset and reversion.	³⁰⁶
MDSCs	lactate metabolism	PKM2, LDHA	Pancreatic cancer	bolster MDSCs and promote a suppressive immune microenvironment	³¹⁴
T cells	lactate metabolism	FIP200	Ovarian cancer	targeting naive T-cells and inhibit FIP200 expression to evade the immune response	³⁰⁷
T cells	lactate metabolism	TCF1	Melanoma, CML	block one-carbon metabolism, decrease H3K27me3 deposition of memory-related genes, thereby affecting differentiation, reserving sternness and facilitating anti-tumor cytotoxicity of T cells	³¹⁸
T cells	lactate metabolism	TCF7, TCF1	CRC	enhance H3K27ac at the TCF7 super-enhancer locus and the stemness of CD8 + T cells	³¹⁶
CD8 + T cells	lactate metabolism	IFNγ, IL-2, TNFα	Breast cancer, CRC	reduce tumor growth, with the effect being dependent on T cells
CD4+/8 + T cells	lactate metabolism	IFN-γ, granzyme B	Melanoma, LLC, colon adenocarcinoma	stimulate the production of antitumor cytokines and reduce tumor growth, with the effect being dependent on T cells	³¹⁵

Abbreviations: ACLY adenosine triphosphate–citrate lyase, AML acute myeloid leukemia, APOC2 apolipoprotein C-II, Arg1 arginase-1, ATP6V0d2 ATPase H+ transporting V0 subunit d2, CD16 cluster of differentiation 16, CD163 cluster of differentiation 163, CD1a cluster of differentiation 1a, CD206 c-type lectin domain family 10 member A, CD63 cluster of differentiation 63, CD80 cluster of differentiation 80, CD86 cluster of differentiation 86, c-JUN Jun proto-oncogene, CML chronic myeloid leukemia, CRC colorectal cancer, DCs dendritic cells, ERK1/2 extracellular signal regulated kinase 1/2, FFA free fatty acids, FIP200 FAK family kinase-interacting protein of 200 kDa, Gpr132 G-protein coupled receptor G2A, H3K18 histone H3 lysine 18, HNSCC head and neck squamous cell carcinoma, IGFBP6 insulin-like growth factor-binding protein 6, LDHA lactate dehydrogenase A, LDHB lactate dehydrogenase B, LLC Lewis lung carcinoma, LUAD lung adenocarcinoma, MDSC myeloid-derived suppressor immune cells, METTL3 methyltransferase like 3, mregDCs mature regulatory DCs, NSCLC non-small cell lung cancer, PKM2 pyruvate kinase M2, RARγ retinoic acid receptor γ, RCC renal cell carcinoma, SLC16A1 solute carrier family 16 member 1, SREBP2 sterol regulatory element-binding protein 2, STAT3 signal transducer and activator of transcription 3, TADC tumor-associated dendritic cells, TCF1 T cell factor 1, TCF7 T cell factor 7, TIMs tumor-infiltrating myeloid cells

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Table 1 Functions of lactate and lactylation in tumor immunity

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