Pancreatic cancer is an aggressive disease with few survivors. The immune response to cancer is helpful in fighting the tumor. By contrast, suppression of the immune response enables cancer progression. The immune response against pancreatic cancer is weak and there is a lack of available drugs to address this problem. The goal of immunotherapy is to enhance the immune response against cancer. Our proposal will provide a new drug for the immunotherapy of pancreas cancer which we will test in mice, in models of human pancreatic cancer, and in a groundbreaking clinical trial. RIP1 is a protein which alters inflammation. We hypothesize that RIP1 suppresses immunity in pancreatic cancer and can be inhibited by a new drug to treat this devastating disease. Our proposal is divided into 3 Aims: Aim 1 will investigate whether RIP1 inhibition using this drug is protective in mouse models of pancreatic cancer. We will also study how the drug acts in the tumor. In Aim 2, we will test our hypothesis that inhibiting RIP1 can treat pancreas cancer in human pancreas cancer models in a dish. In Aim 3 we will test whether RIP1 inhibition is safe and shrinks tumors in pancreatic cancer patients in a Phase 1 clinical trial. We will also assess changes in immunity against cancer following RIP1 inhibition using protein and DNA-based methods. In summary, our work will detail the means by which RIP1 suppresses immunity in pancreas cancer and investigate the effectiveness of inhibiting RIP1 in a cutting-edge clinical trial.