PGK1 epigenetically silences STING via DNMT1 and its knockdown synergizes with STING agonists in pancreatic cancer.

The highly immunosuppressive tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) severely limits the efficacy of current immunotherapies. Identifying key molecular drivers of this immunosuppressive niche is therefore essential for developing new treatment strategies. In this study, through comprehensive bioinformatic analysis of PDAC clinical datasets and systematic experimental validation, we demonstrate that PGK1 is upregulated in PDAC and is associated with poor immune infiltration. Genetic knockdown of PGK1 upregulated STING expression, promoted the recruitment of antitumor immune cells into the tumor microenvironment, and significantly enhanced the in vivo efficacy of STING agonist treatment. Mechanistically, PGK1 stabilizes DNMT1 by blocking its ubiquitination-mediated degradation, which in turn promotes methylation of the STING promoter and suppresses its transcription. Our findings reveal a non-metabolic role of PGK1 in promoting an immunosuppressive microenvironment and propose a promising combination strategy targeting the PGK1-STING axis for the treatment of PDAC.