Fig. 1

Abnormal tumor vasculature triggers immunosuppression in the tumor microenvironment (created with BioRender.com). Malformed and dysfunctional vascular systems in breast cancer cause perfusion restriction, leading to hypoxia and acidosis in the TME. Tumor vasculature abnormalities promote immunosuppression through multiple mechanisms. VEGF induces tumor angiogenesis, and tumor vascular endothelial cells with PD-L1 and Fas-L expression recruit immunosuppressive cells. CSF1, TGF-β, and CXCL12 polarize TAMs from a protumorigenic M1-like phenotype into an antitumorigenic M2-like phenotype. VEGF, CXCL8, and CXCL12 inhibit DC maturation, resulting in impaired antigen presentation and leading to disrupted T cell activation. TGF-β and IL-10 induce CD8⁺ T cell exhaustion, and TGF-β inhibits NK cell function. Tregs and MDSCs accumulate, activate, and expand in the TME. The CAFs in the TME promote tumor angiogenesis by producing VEGF, PDGF-c, PDPN, and MMP13. The PD-L1 pathway is normally activated as a mechanism to evade the antitumor immune response. Overall, aberrant tumor angiogenesis results in an immunosuppressive TME. ANG2, Angiopoietin 2; CAFs, Cancer-associated fibroblast; CCL28, CC chemokine ligand 28; CXCL8, CXC chemokine ligand 8; CXCL12, CXC chemokine ligand 12; CSF1, Colony-stimulating factor 1; DC, Dendritic cell; Fas-L, FAS antigen ligand; FGF, Fibroblast growth factor; MMP, Matrix metallopeptidase; NK, Natural killer; PD-1, Programmed cell death protein 1; PD-L1, Programmed cell death 1 ligand 1; PDGF, Platelet-derived growth factor; PDPN, Podoplanin; ROS, Reactive oxygen species; TAM, Tumor-associated macrophage; TGF-β, Transforming growth factor beta; TME, Tumor microenvironment; Tregs, Regulatory T cells; VEGF, Vascular endothelial growth factor