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.

Table 2 Ongoing or completed clinical trials of anti-angiogenic therapy in combination with immunotherapy

Inhibitor	Clinical stage	Study status	Conditions	Intervention	Ref.
Anlotinib	II	Recruiting	NSCLC	In combination with penpulimab	NCT06341530
	II	Recruiting	Breast cancer	In combination with sintilimab and chemotherapy	NCT04877821
Apatinib	II	Ongoing	Solid tumor	In combination with adebrelimab and microwave ablation	NCT06537505
Axitinib	II	Completed	Advanced melanoma	In combination with nivolumab	NCT04493203
Bevacizumab	I/II	Completed	Malignant solid tumor	In combination with NK immunotherapy	NCT02857920
	II	Completed	Colorectal cancer	In combination with atezolizumab and chemotherapy	NCT02873195
	I/II	Recruiting	Ovarian cancer	In combination with oregovomab and chemotherapy	NCT04938583
	II/III	Recruiting	Colorectal cancer liver metastases	In combination with serplulimab and chemotherapy	NCT06280495
	II	Recruiting	Gastric cancer	In combination with neoadjuvant chemotherapy and PD-1 mAb	NCT06371586
	II	Recruiting	Recurrent TNBC	In combination with pembrolizumab and chemotherapy	NCT06976944
	IV	Ongoing	Advanced melanoma	In combination with iparomlimab and tuvonralimab	NCT07004335
Ramucirumab	II	Recruiting	Gastric cancer	In combination with pembrolizumab and chemotherapy	NCT04069273
Sorafenib	II	Completed	Hepatocellular carcinoma	In combination with PD-1 mAb	NCT04518852

NSCLC: Non-small cell lung cancer; NK: Natural killer; PD-1: Programmed cell death-1; mAb: Monoclonal antibody; TNBC: Triple negative breast cancer.