Researchers used a CRISPR/Cas9 genome-wide screen to identify SUV39H2, a histone methyltransferase, as a key driver of resistance to oncolytic herpes simplex virus 1 (oHSV-1) therapy in oral squamous cell carcinoma (OSCC). Targeting SUV39H2 could enhance the efficacy of viral-based cancer therapies, providing a new avenue for treatment of resistant OSCC tumors. This molecular insight offers potential for precision oncology strategies.