Fig. 3

The abnormal tumor vessels lead to immunosuppression in TME. Abnormal tumor vessels contribute to a hypoxic, acidic TME, as well as high levels of pro-angiogenic factors such as VEGF, which result in immunosuppression. These mechanisms include increasing the accumulation of immunosuppressive Treg cells and MDSCs, promoting the accumulation of TAMs and the polarization towards the pro-tumor M2 phenotype, inhibiting DCs maturation, leading to impaired antigen presentation, inhibiting CTLs activation. Hypoxia can also directly limit CTLs function. Tumor vascular ECs also exhibit immunosuppressive phenotypes, reducing the infiltration of CTL into tumor tissue. In addition, inhibitory immune checkpoint pathways are generally activated in TME to limit the anti-tumor function of CTLs. PD-L1 expression was up-regulated in TAMs, DCs, ECs, and tumor-infiltrating CTLs usually up-regulated PD-1 and other inhibitory immune checkpoint receptors, indicating their dysfunction or failure and limiting their killing ability to tumor cells. CTL cytotoxic T lymphocyte, Treg cell regulatory T cell, DC dendritic cells, MDSCs myeloid-derived suppressor cells, TAM tumor-associated macrophage, PD-1 programmed cell death 1, PD-L1 programmed cell death ligand 1, FasL Fas ligand, CTLA-4 cytotoxic T-lymphocyte-associated protein 4