To achieve stronger antitumor effects, this study incorporated single agents, double, and triple combinations of synthetic innate agonists including both STING and NLRP3 agonists, chemotherapy, and ICIs in randomized studies in both pancreatic orthotopic syngeneic mouse models and genetically engineered spontaneous tumor models of pancreatic cancer resembling clinical trials of human PDAC patients. Here, NLRP3 is linked to familial pancreatic carcinoma.