Abstract B029: TAK1 blockade induces DNA damage and immunogenic cGAS–STING pathway activation in pancreatic cancer

Abstract Dysregulation of the Transforming Growth Factor-β (TGF-β) pathway contributes to the immunologically “cold” tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC), yet TGF-β receptor inhibitors have not succeeded clinically. We identify TGF-β-activated kinase 1 (TAK1/MAP3K7), a component of non-canonical TGF-β signaling, as aberrantly activated in human and mouse PDAC and associated with T cell dysfunction. Inhibiting TAK1 pharmacologically (with Takinib) or genetically in autochthonous PDAC mice enhances T cell infiltration, reduces immunosuppressive macrophages, and sensitizes tumors to immune checkpoint blockade (ICB). TAK1 inhibition induces DNA damage and leakage into the cytoplasm, which activates the cGAS–STING pathway, promoting inflammation and adaptive immunity. Mechanistically, we found that TAK1 phosphorylates EphA2 (Ser897), which in turn phosphorylates RAD51 (Tyr315), a critical driver of homologous recombination repair. Our findings reveal a novel role for TAK1 in maintaining genomic integrity and underscore its therapeutic potential in reprogramming the TME to sensitize PDAC to ICB. Citation Format: Sapana P. Bansod, Timothy Hung-Po Chen, Vikas Somani, Lin Li, Suneeta Modekurty, Brett Knolhoff, Ryan Fields, Marianna Ruzinova, David DeNardo, Kian-Huat Lim. TAK1 blockade induces DNA damage and immunogenic cGAS–STING pathway activation in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B029.