Through a comprehensive workflow combining H3K27ac-ChIP-seq and RNA-seq analyses, we identified critical TFs and tumor-specific super-enhancer domains (T-SEDs) that regulate gene expression in HPV+ HNSCC, such as TP63, SMAD3, FOSL2, JUND, JUNB, KLF5, and TFAP2A. Here, SMAD3 is linked to neoplasm.