We have previously shown that the protein methyltransferase SMYD3 represses tumor intrinsic interferon responses in HPV-negative HNSCC through direct transcriptional activation of the H3K9me3-reader UHRF1 which recruits DNMT1A, as well as by promoting the deposition of the repressive mark H4K20me3 on immune-related genes, thus exerting a bifaceted function as a transcription regulator12. Here, SMYD3 is linked to head and neck squamous cell carcinoma.