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BACKGROUND AND AIMS Checkpoint immunotherapy is largely ineffective in pancreatic ductal adenocarcinoma (PDAC). The innate immune NF-κB pathway promotes PDAC cell survival, stromal fibrosis and is driven by IRAK4, but its impact on tumor immunity has not been directly investigated. METHODS We interrogated the TCGA data to identify the correlation between NF-κB and T cell signature, and a PDAC tissue microarray (TMA) to correlate IRAK4 activity with CD8+ T cells abundance. We performed RNAseq on IRAK4-deleted PDAC cells, and single cell RNAseq on autochthonous KPC (p48-Cre/TP53f/f/LSL-KRASG12D) mice treated with an IRAK4 inhibitor. We generated conditional IRAK4-deleted KPC mice and complementarily used IRAK4 inhibitors to determine the impact of IRAK4 on T cell immunity. RESULTS We found positive correlation between NF-κB activity, IRAK4 and T cell exhaustion from TCGA. We observed inverse correlation between phosphorylated IRAK4 and CD8+ T cell abundance in a PDAC TMA. Loss of IRAK4 abrogates NF-κB activity, several immunosuppressive factors, checkpoint ligands and hyaluronan synthase 2 (HAS2), all of which drive T cell dysfunction. Accordingly, conditional deletion or pharmacologic inhibition of IRAK4 markedly decreased tumor desmoplasia and increased the abundance and activity of infiltrative CD4+ and CD8+ T cells in KPC tumors. Single cell RNAseq showed myeloid and fibroblast reprograming towards acute inflammatory responses following IRAK4 inhibition. These changes set the stage for successful combination of IRAK4 inhibitors with checkpoint immunotherapy, resulting in excellent tumor control and markedly prolonged survival of KPC mice. CONCLUSION IRAK4 drives T cell dysfunction in PDAC and is a novel, promising immunotherapeutic target.