VISTA as a tumour-microenvironment checkpoint: spatial, metabolic and cellular control of antitumour immunity
- 1Department of Thoracic Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China (Sichuan Cancer Hospital)
- 2Department of Thoracic Surgery I, Key Laboratory of Lung Cancer of Yunnan Province, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital)
- 3Department of Radiology, The Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital)
Abstract
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.
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BibTeX
@article{li2026vista,
title = {{VISTA as a tumour-microenvironment checkpoint: spatial, metabolic and cellular control of antitumour immunity}},
author = {Kexun Li and Zilong Qian and Jianzhe Zhang and Jie Mao and Tengfei Ke},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1901272},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1901272/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - VISTA as a tumour-microenvironment checkpoint: spatial, metabolic and cellular control of antitumour immunity
AU - Kexun Li
AU - Zilong Qian
AU - Jianzhe Zhang
AU - Jie Mao
AU - Tengfei Ke
PY - 2026
DA - 2026/10/14
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1901272
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1901272/full
AB - 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.
SN - 1664-3224
ER -