Combined targeted and epigenetic-based therapy enhances antitumor immunity by stabilizing GATA6-dependent MHCI expression in pancreatic ductal adenocarcinoma
- JuanFei Peng
- JiaJin Yang
- Georgia Antonopoulou
- Rui Fang
- Bikash Adhikari
- Markus Vogt
- Elmar Wolf
- Chong Sun
- Shangce Du
- Laura Godfrey
- Aayush Gupta
- Marija Trajkovic-Arsic
- Nicole Teichmann
- Barbara T. Grünwald
- Niklas Krebs
- Katja Steiger
- Carolin Mogler
- Kristina Althoff
- Xin Wang
- Giovanni Giglio
- Sven-Thorsten Liffers
- Konstantinos Savvatakis
- Rickmer Braren
- Rita T. Lawlor
- Aldo Scarpa
- Diana Behrens
- Karl S. Lang
- Phyllis F. Cheung
- Jens T. Siveke
2026-02-06
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.