Abstract The study by Gonda and colleagues, in this issue of Cancer Research, represents the first combinatorial approach based on epigenetic therapy priming to overcome resistance to immunotherapy in pancreatic cancer. The authors show that treatment with a DNA hypomethylating agent causes profound changes in the pancreatic cancer microenvironment, including increased numbers of tumor-infiltrating T cells, elevated IFN signaling, and immune checkpoint expression, as well as increased antigen presentation in tumor cells. Accordingly, they show that the combination of decitabine plus immune checkpoint blockade effectively restores antitumor immunity and results in a significant survival benefit in a widely accepted mouse model of pancreatic cancer. The study provides evidence for a new therapeutic approach for pancreatic cancer having antitumor efficacy through modulation of the immune suppressive microenvironment, leading to an increased response to immune checkpoint inhibitors. As the incidence of pancreatic cancer continues to increase, new treatment strategies for this devastating disease are urgently needed. Gonda and colleagues provide preclinical proof of concept for a new therapeutic strategy and address an unmet need for this difficult to treat disease. See related article by Gonda et al., p. 4754