Loss of ADAR1 in tumor cells activates cDC1s and sensitizes pancreatic cancer to immunotherapy

Pancreatic cancer is notoriously resistant to immunotherapy, primarily due to inadequate antigen presentation and the exclusion of immunogenic cells from the tumor microenvironment. Strategies to enhance antigen presentation and promote the infiltration of cytotoxic CD8+ T cells may improve the efficacy of immunotherapy in pancreatic cancer. In this study, we show that ADAR1 is overexpressed in pancreatic cancer, and higher ADAR1 expression correlates with poorer survival outcomes in patients. Depletion of ADAR1 in tumor cells leads to an accumulation of endogenous double-stranded RNA (dsRNA), which triggers the MDA5-mediated type I interferon (IFN) response and results in excessive IFNβ production. Tumor-derived IFNβ then promotes the recruitment and activation of cDC1s, thereby enhancing CD8+ T cell infiltration and activation, and ultimately sensitizing pancreatic cancer to CD8+ T cell-based immunotherapy. These findings suggest that combining ADAR1 inhibition with immunotherapy may offer a promising therapeutic strategy for pancreatic cancer.