Mechanistically, hypoxic condition induces activation of hypoxia-inducible factor (HIF) proteins that enhance tumor cell or MDSCs expression of immune checkpoint receptors PD-1 and V-domain Ig suppressor of T cell activation (VISTA), macrophage immune checkpoint CD47, nonclassical MHC-I molecules, human leukocyte antigen (HLA)-G and HLA-E, as well as Tregs recruitment, resulting in the release of immunosuppressive metabolites (179). Here, VSIR is linked to neoplasm.