In conclusion, we identify that GNAS KO is a sensitizer of resistant lymphoma cells to HDAC3 inhibition via viral mimicry-related IFN responses and can enhance CD8+ T cell-induced cytotoxicity with HDAC3 inhibition, and further demonstrate a potential viral mimicry priming role of low GNAS expression in DLBCL patients. Here, CD8A is linked to diffuse large B-cell lymphoma.