Here, through genome-wide CRISPR/Cas9 library screening, Suppressor of variegation 3–9 homolog 2 (SUV39H2), a histone methyltransferase, was identified as a critical factor in mediating resistance to oncolytic herpes simplex virus 1 (oHSV-1) in oral squamous cell carcinoma (OSCC). This evidence concerns the gene SUV39H2 and oral cavity squamous cell carcinoma.