VISTA drives pancreatic tumor progression through modulation of the tumor-associated macrophage polarity

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.