DNA polymerase mutations can cause hypermutant cancers, but the mechanisms of tumorigenesis and the impact of various DNA polymerase mutations on treatment response is poorly understood. In this issue of Cancer Research, Galati and colleagues investigate the effects of cancer-associated DNA polymerase ϵ (Pole) mutations on tumorigenesis and response to immune checkpoint blockade. They describe novel genetically engineered mouse models harboring cancer-associated Pole mutations and examine the effects of these mutations on tumorigenesis, the tumor mutational landscape, and the tumor immune microenvironment. Integrating this information with an emerging understanding of how different tumor mutations influence the response to immunotherapy may aid in prediction, diagnosis, and treatment of Pole-mutant tumors.See related article by Galati et al., p. 5606.