Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies due to its highly immunosuppressive tumor microenvironment (TME), which limits effective therapeutic interventions. Here, we demonstrate that V-domain immunoglobulin suppressor of T cell activation (VISTA) plays a crucial role in orchestrating macrophage polarity within the PDAC TME. Using murine PDAC models, we show that VISTA deficiency markedly impairs tumor growth, leading to prolonged survival. Functionally, VISTA deficiency is linked to a shift in tumor-associated macrophages (TAMs) from an immunosuppressive phenotype marked by secreted phosphoprotein 1 (SPP1), to one enriched for C-X-C motif chemokine ligand 9 (CXCL9), indicative of a pro-inflammatory state. This shift is accompanied by enhanced recruitment of CXCR3⁺ CD8⁺ T cells with sustained cytotoxic potential, among which terminal exhaustion-like CD8+ T cell states are less prevalent. Additionally, VISTA-deficient TAMs exhibit increased antigen cross-presentation, further amplifying CD8+ T cell response against tumors. These findings are corroborated by human PDAC data, which reflect similar immune reprogramming trends. By defining the role of VISTA in controlling Cxcl9:Spp1 ratio and modulating CD8⁺ T cell dynamics, this study positions VISTA inhibition as a promising strategy to reshape the TME and potentiate anti-tumor immunity in PDAC.
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Data availability
The single-cell RNA sequencing data generated in this study have been deposited in NCBI Gene Expression Omnibus (GEO) under the accession code GSE282101. The publicly available TCGA-PAAD dataset used in this study can be accessed via the GDC Data Portal [https://portal.gdc.cancer.gov/projects/TCGA-PAAD]. Source data are provided with this paper.
Code availability
All custom-written code can be accessed at [https://github.com/gracesshin/VISTA_PDAC].
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Acknowledgements
Figures 7a and 7c were created with BioRender.com. This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (No. RS-2024-00406325 to D.-S.L.). This research was also supported by the National Research Foundation of Korea (NRF) grant, funded by the Korea government (MSIT) (No. RS-2024-00345658 and RS-2025-25403101 to D.-S.L.) and by the Education and Research Encouragement Fund of Seoul National University Hospital. Suk-Kyung Shin was supported by BK21 Four Biomedical Science Program, Seoul National University College of Medicine.
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S.-K.S. conceived and designed the study, performed experiments, analyzed murine single-cell data, and wrote the manuscript. G.K. performed and led the analysis of murine and human single-cell data and contributed to manuscript revision. G.H.K. guided human tissue staining and performed human IHC scoring. K.J. provided key reagents and methodological support. S.M.P. assisted with experiments. E.-B.S., S.-K.Y., and H.M.S. contributed to data discussion and manuscript revision. H.-R.K. and D.-S.L. supervised the study and edited the manuscript. All authors discussed the results and commented on the manuscript.
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Shin, SK., Kim, G., Park, S.M. et al. VISTA drives pancreatic tumor progression through modulation of the tumor-associated macrophage polarity. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70215-7
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DOI: https://doi.org/10.1038/s41467-026-70215-7
