Endothelial metabolic reprogramming influences tumor immune microenvironment

Figure 3 Endothelial metabolic reprogramming alters the tumor immune microenvironment. In the tumor microenvironment (TME), endothelial cells undergo metabolic reprogramming, including enhanced glycolysis, fatty acid oxidation and glutaminolysis. These alterations will not only affect the proliferation and migration of endothelial cells, but also have an impact on immune cells in the TME. The expression of programmed death-ligand 1 is increased on tumor endothelial cell (TEC), which in turn induces CD8+ T cell suppression. TECs induce the exhaustion of CD8+ T cells via glycoprotein nonmetastatic melanoma protein B. Moreover, they secrete C-X-C motif ligand 12 (CXCL12) to impede the differentiation of naïve CD8 T cells into cytotoxic T cells. TECs can also recruit regulatory T cells, tumor-associated macrophages, tumor-associated neutrophils and myeloid-derived suppressor cells to the TME by secreting factors including C-C motif ligand 2, CXCL1, CXCL2 and granulocyte colony-stimulating factor. This process contributes to the establishment of an immunosuppressive state. Furthermore, TECs secrete CXCL2 and CXCL4, which drive the polarization of macrophages towards the M2 phenotype. The accumulation of immunosuppressive cells within the TME leads to the further secretion of pro-angiogenic factors, thereby inducing abnormal angiogenesis. The structurally and functionally dysregulated blood vessels exacerbate the hypoxic condition of the TME, which in turn further promotes the metabolic reprogramming of TECs. MDSCs: Myeloid-derived suppressor cells; TME: Tumor microenvironment; TEC: Tumor endothelial cell; CCL2: C-C motif ligand 2; CXCL1: C-X-C motif ligand 1; G-CSF: Granulocyte colony-stimulating factor; VEGF: Vascular endothelial growth factor; JAK: Janus kinase; STAT: Signal transducer and activator of the transcription; NK: Natural killer; GPNMB: Glycoprotein non-metastatic melanoma protein B; PD-L1: Programmed death-ligand 1; Treg: Regulatory T; FAO: Fatty acid oxidation; ox-LDL: Oxidized low-density lipoprotein; LOX-1: Lectin-like oxidized low-density lipoprotein receptor-1; TAN: Tumor-associated neutrophil.