Targeting tumor-intrinsic TAK1 triggers anti-tumor immunity and sensitizes pancreatic cancer to checkpoint blockade.

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: We developed a novel tumor-CD8 T cell co-culture to interrogate the TGF-β signaling pathways that promotes T cell-mediated cytotoxicity. We performed multiplex immunohistochemistry (mIHC) on human PDAC samples to correlate cell-type specific TGF-β pathway activation and CD8 T cell abundance. We employed specific pathway inhibitor and newly generated genetically-engineered mouse models (GEMMs) and confirmed our findings using single-cell RNA sequencing, flow cytometry and mIHC. We performed proteomics and various in vitro assays to establish the molecular mechanisms. Results: We identify TGF-β-activated kinase 1 (TAK1 or MAP3K7) as an aberrantly activated kinase in human and mouse PDAC tissues that is associated with T cell dysfunction. Pharmacological inhibition of TAK1 with Takinib, or genetic deletion of 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.