Metformin activates the STING/IRF3/IFN-β pathway by inhibiting AKT phosphorylation in pancreatic cancer

The anti-diabetes drug metformin has emerged as a promising antitumor agent in pancreatic ductal adenocarcinoma (PDAC) among other cancers by promoting the infiltration of immune cells in the tumor microenvironment (TME). However, the mechanisms underlying the antitumor effects of metformin in PDAC remain unclear. In this study, we revealed that metformin induced stimulator of interferon genes (STING) expression in pancreatic cancer cells in a dose- and time-dependent manner. Metformin also activated the STING/IRF3/IFN-beta pathway by inhibiting AKT signaling in PDAC cells. Importantly, the combination of metformin with the STING agonist 2'3'-cGAMP exerted synergistic effects in activatingthe STING/IRF3/IFN-beta pathway in pancreatic cancer cells. Additionally, metformin augmented the antitumor effects of 2'3'-cGAMP in mouse models by enhancing the infiltration of T cells in the TME. These findings unveiled a previously unknown mechanism contributingto the antitumor effects of metformin in PDAC, and provide a rationale for its use in combination with existing or novel immunotherapies.