Abstract: In recent years, the diversity of proteins and complexity of gene regulation associated with RNA editing dysregulation has been increasingly appreciated in oncology. By profiling editing in single cells from lung cancer biopsies, we found that the increased editing trend of bulk lung tumors was unique to cancer cells. Elevated editing levels were observed in cancer cells resistant to targeted therapy, and editing sites associated with drug response were enriched. Consistent with the regulation of antiviral pathways by RNA editing, we observed that higher editing levels in cancer cells were associated with reduced anti-tumor innate immune response. In addition, the level of RNA editing in cancer cells was positively associated with somatic point mutation burden. Building upon these discoveries, we have developed new methods and materials that can be used to identify RNA mutations that correlate with tumor mutation burden and cancer innate immunity.