Abstract 3769: Targeting TAK1 kinase triggers anti-tumor immunity and sensitizes pancreatic cancer to checkpoint blockade

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers with limited effectiveness to immune checkpoint therapies, primarily due to its immunological “cold” tumor microenvironment (TME). We identified overactivation of phosphorylated Transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1 a. k. a. MAP3K7) kinase during development of pancreatic cancer in Human and mouse PDAC models. We demonstrated that phospho-TAK1 activity was increased in human PDAC TMA tissues, and it’s correlated with high levels of TGFB and less CD8+ cytotoxic T cell abundance. The pharmacological inhibition of the TAK1 using selective TAK1 inhibitor Takinib significancy reduces tumor progression, prolong overall survival, enhances intratumoral CD4+ and CD8+ effector T cells, and decreases myeloid infiltration in the p48-Cre/TP53f/f/LSL-KRASG12D (KPC) mouse PDAC model. Further, genetic or pharmacologic inhibition of TAK1 enhances the sensitivity of PDAC to immune checkpoint blockade (anti-PD-1 and anti-CTLA4), leading to significant reduction in tumor desmoplasia and extended survival in KPC mice. Mechanistically, inhibition of TAK1 in PDAC cells triggers cGAS-STING signaling by inducing cytosolic DNA damage which facilitates cytotoxic CD8+ T cell-dependent cell death. Together, our data provide the rationale for combining TAK1 inhibition with immune checkpoint blockade (anti-PD-1 and anti-CTLA4) as a therapeutic strategy for PDAC patients. Citation Format: Sapana P. Bansod, Vikas Somani, Hung-Po Chen, Lin Li, John Baer, David G. DeNardo, Kian-Huat Lim. Targeting TAK1 kinase triggers anti-tumor immunity and sensitizes pancreatic cancer to checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3769.