Together, our results indicate that the combination of ACY-241 and JQ1 suppresses TNF-α-induced responses by dysregulating MT1-MMP, MMP-2, and MMP-9 and by modulating AKT/NF-κB signaling pathways in both HPV-positive and HPV-negative HNSCC cells. Here, MMP2 is linked to head and neck squamous cell carcinoma.