Endothelial metabolic reprogramming influences tumor immune microenvironment

Table 1 Specific inhibition of endothelial glycolysis, lipid metabolism, amino acid metabolism and oxidative phosphorylation as novel targets for antitumor therapy

Metabolic type	Target	Agent	Conditions	Mechanism	Ref.
Glycolysis	PFKFB3	PFK15	Hepatocellular carcinoma	Suppressing glycolysis in TECs and tumor cells and inducing apoptosis. Inducing tumor vessel normalization	[28]
		Apatinib	Hepatocellular carcinoma	Suppressed glycolysis in ECs via blocking PI3K/AKT/PFKFB3 pathway	[113]
		3PO	Pathological neovascularization	Inhibiting glycolysis in ECs partially and reversibly. Enhancing the antiangiogenic efficacy of VEGF blockade	[114]
	PKM2	SAA	Melanoma and lung cancer	Reducing glycolysis in ECs and activating the PKM2-dependent β-catenin/claudin-5 signaling axis improves endothelial integrity	[115]
Fatty acid metabolism	FASN	Orlistat	Retinopathy of prematurity	Inhibiting pathologic ocular neovascularization by decreasing mTOR activity	[56]
		Orlistat	Melanoma	Reducing HDLEC cells proliferation and migration. Inhibiting the secretion of VEGF-C and promoted the secretion of VEGF-D by melanoma cells	[57]
	CPT1	Etomoxir	Lymphangiogenesis	Inhibiting injury-induced lymphangiogenesis	[119]
Glutamine metabolism	GLS	miR-367b-3p	Choroidal neovascularization	Inhibiting CEBPB leads to the inactivation of GLS1 transcription. Inhibiting ECs proliferation, migration and tubular structure formation while promoting apoptosis	[122]
	GS	MSO	Lung cancer	Inducing a shift from the M2 phenotype to the M1 phenotype in macrophages. Promoting tumor vessel normalization and inhibiting the metastasis of cancer cells	[124]
OXPHOS	Mitochondria	Embelin	Pathological neoangiogenesis in tumor and injury	Depleting the low respiratory reserve of proliferating ECs without deleterious effects on resting ECs	[44]

PFKFB3: 6-phosphofructo-2-kinase/fructose-2,6-bisphosph-atase 3; PFK15: Phosphofructokinase-15; TECs: Tumor endothelial cells; ECs: Endothelial cells; PI3K: Phosphoinositide 3-kinases; AKT: Protein kinase B; 3PO: 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one; VEGF: Vascular endothelial growth factor; PKM2: Pyruvate kinase M2; SAA: Salvianic acid A; FASN: Fatty acid synthase; mTOR: Mammalian target of rapamycin; HDLEC: Human lymphatic endothelial cell; CPT1: Carnitine palmitoyltransferase 1; GLS: Glutaminase; CEBPB: CCAAT/enhancer-binding protein beta; GS: Glutamine-synthetase; OXPHOS: Oxidative phosphorylation.