By leveraging murine MOC1 and MOC2 cell-derived tumors with differential dendritic cell and T-cell infiltration, our findings suggest that impaired DNA sensing through the cGAS-IFN-I signaling pathway in “immune-cold” HNSCC cells may contribute to antigen presentation dysfunction and DC deficiency, leading to immune evasion and therapeutic resistance to immunotherapy. Here, CGAS is linked to head and neck squamous cell carcinoma.