Abstract Summary: Cancer genetic alterations and epigenetics control the malignant phenotype of tumor cells and the stroma. Synergistic oncogenic alterations may cooperatively dictate immunogenicity, level of infiltration by immune system cells, and response to immunotherapy in an epistatic fashion. The work of Skoulidis and colleagues shows that concomitant RAS and STK11/LKB1 mutations in non–small cell lung adenocarcinomas result in primary resistance to PD-1–based immunotherapy and poor T-cell infiltration. Cancer Discov; 8(7); 794–6. ©2018 AACR. See related article by Skoulidis et al., p. 822.