Through genetic depletion using siRNAs and clustered regularly interspaced short palindromic repeats (CRISPR) editing, pharmacological inhibition, and high-throughput genome-wide mapping of H4K20me3 through cleavage under targets and release using nuclease (CUT&RUN) assays, we unveil the role of SUV420H1 as an oncogene and immunomodulator in HPV-negative HNSCC. The gene discussed is KMT5B; the disease is head and neck squamous cell carcinoma.