VISTA as a tumour-microenvironment checkpoint: spatial, metabolic and cellular control of antitumour immunity

V-domain immunoglobulin suppressor of T-cell activation (VISTA; also termed VSIR, PD-1H or B7-H5) is increasingly recognised as an immune checkpoint whose biological and clinical significance depends less on total expression than on the tumour microenvironment (TME) in which it operates. Rather than acting as a linear T-cell exhaustion receptor, VISTA integrates tumour chemistry, stromal architecture, innate and adaptive immune states, and therapy-induced feedback inhibition. It is expressed by tumour cells and multiple immune populations, including macrophages, myeloid-derived suppressor cells, dendritic cells, neutrophils, regulatory T cells and activated or quiescent T cells. VISTA can also function through pH-dependent and pH-independent ligand-receptor interactions. This review reframes VISTA as a TME-gated regulatory system. Low pH, hypoxia, transforming growth factor beta (TGF-β), histamine, aldehyde metabolism, Yes-associated protein (YAP)/TEA domain (TEAD) signalling, macrophage polarity, antigen-presenting-cell fitness and spatial immune exclusion can jointly determine whether VISTA marks immune resistance, immune activation under feedback restraint or tumour-cell-intrinsic evasion. This context helps explain the divergent prognostic associations of VISTA across pancreatic, gastric, colorectal, lung, breast, bladder, gynaecological, skin, brain, mesothelial and haematological malignancies. Therapeutically, VISTA should therefore not be treated as another universal immune-checkpoint target. More plausible strategies include pH-selective antibodies, ligand-axis disruption, local or nanoparticle delivery, targeted degradation, tumour-cell-intrinsic pathway inhibition and combinations that convert suppressive TME niches into antigen-presenting and cytotoxic niches. A TME-centred framework can make VISTA biology clinically interpretable and guide biomarker development, trial design and rational combination immunotherapy.