Oncolytic herpes simplex virus-1 (oHSV) is FDA-approved for melanoma1, 2 and conditionally approved for glioblastoma (GBM); however, clinical responses remain limited.3 Resistance arises from both tumor-intrinsic and -extrinsic mechanisms, including dysregulated interferon signaling, aberrant growth factor pathways, and pronounced tumor heterogeneity.4, 5 Moreover, oHSV can paradoxically suppress anti-tumor immunity and activate pro-survival pathways such as PI3K/AKT and mTORC1, promoting tumor persistence.6, 7. The gene discussed is AKT1; the disease is neoplasm.