We provide new information on three mechanisms, whereby IFN-I exposure can enhance NK cell activity against both oncolytic virus infected cells and non-infected cells: (1) generate an antiviral state in NK cells which prevents off-target infection and virus-induced cytopathic effects, (2) increase inherent cell killing capacity of PM21-NK cells through pathways at least in part involving TRAIL, and (3) reduce IFN-γ production. This evidence concerns the gene TNFSF10 and infection.