Blockade of Tumor TAK1 Induces DNA Damage and Immunogenic cGAS–STING Pathway Activation in Pancreatic Cancer

BACKGROUND AND AIMS: Targeting the Transforming Growth Factor-β (TGF-β) pathway to reverse the immunologically "cold" tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) remains clinically unsuccessful, warranting novel therapeutic strategies. METHODS: T cell abundance and developed a tumor and T cell co-culture to interrogate the TGF-β pathways that promotes T cell-mediated cytotoxicity. We employed newly generated genetically-engineered mouse models (GEMMs) and specific pathway inhibitor and confirmed our findings using single-cell RNA sequencing, flow cytometry and mIHC. We performed proteomics and various in vitro and in vivo assays to establish the mechanisms. RESULTS: effector T cell infiltration and renders immune checkpoint blockade (ICB) effective. Mechanistically, TAK1 inhibition induces DNA damage and cytoplasmic DNA leakage, which activates the cyclic GMP-AMP synthase-Stimulator of Interferon Genes (cGAS-STING) DNA sensing pathway, triggering inflammatory responses that promote adaptive immune cell infiltration. At the molecular level, TAK1 phosphorylates Ephrin Receptor A2 (EphA2) at Serine 897, which in turn phosphorylates RAD51 at Tyrosine 315, a key DNA repair protein involved in homologous recombination. CONCLUSIONS: We uncover TAK1 as a critical mediator in maintaining genomic integrity and highlights its potential as a therapeutic target to induce an inflamed TME that sensitizes PDAC to ICB.