A genome-wide CRISPR/Cas9 screen revealed SUV39H2, a histone methyltransferase, as a key mediator of resistance to oncolytic herpes simplex virus 1 (oHSV-1) in oral squamous cell carcinoma (OSCC). This discovery provides valuable insight into viral resistance mechanisms and may inform the development of enhanced viral-based cancer therapies. The findings, published in Cell Death Discovery, highlight epigenetic factors as potential therapeutic targets to improve oncolytic virus efficacy in OSCC.