Combined targeted and epigenetic-based therapy enhances antitumor immunity by stabilizing GATA6-dependent MHCI expression in pancreatic ductal adenocarcinoma

GATA6 promotes epithelial phenotypes and limits epithelial-to-mesenchymal (EMT) transition in pancreatic ductal adenocarcinoma (PDAC). Here we show that GATA6 defines a tumor cell state that induces MHCI expression and anti-tumor cytotoxicity upon therapy. In human PDAC, GATA6 expression correlates with immune cell infiltration, and spatial analysis reveals interaction between GATA6 + tumor cells and CD8 + T cells. In murine PDAC, MEK inhibition (MEKi) enriches antigenicity-related gene sets in GATA6 high cells, while GATA6 knockout or degradation impairs MEKi-induced MHCI upregulation. High-GATA6 tumors respond to MEKi with increased MHCI, enhancing T-cell cytotoxicity, whereas GATA6 loss abolishes this effect. Treatment-induced EMT reduces GATA6 + populations and MHCI expression, which is restored by combining MEKi with HDAC inhibitors, enhancing GATA6 + tumor cells, MHCI, CD8 + T cell infiltration, tumor suppression, and survival. These findings suggest that therapeutic strategies promoting a GATA6-driven tumor cell state improve immune recognition of PDAC cells and potentiate anti-tumor cytotoxic effects.