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Objective: To investigate the differences in apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) between human papillomavirus (HPV)-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) patients, analyze its association with the immune microenvironment and the cGAS-STING pathway, and evaluate its predictive value for immunotherapy efficacy. Methods: Whole-exome sequencing data from HNSCC patients (from September 2017 to March 2020 at the Third Affiliated Hospital of Kunming Medical University) were collected for somatic mutation profiling. APOBEC enrichment scores were calculated and integrated with differentially expressed genes (DEGs) to perform Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Gene Set Enrichment Analysis (GSEA). Single-cell RNA sequencing (scRNA-seq) data were utilized to validate the relationship between APOBEC3 expression, immune cell composition, and cGAS-STING module activity. Furthermore, an immunotherapy cohort was analyzed to evaluate the association of APOBEC3 family gene expression with immune checkpoint genes and therapeutic outcomes. Results: APOBEC mutational signatures were prevalent in both HPV-negative and HPV-positive HNSCC patients, but their driving patterns differed significantly: HPV-positive patients were dominated by APOBEC3A mutations, whereas the HPV-negative group exhibited a synergistic effect of multiple family members, including APOBEC3A/3B/3C/3D/3F. Pathway analysis indicated that in HPV-negative HNSCC, APOBEC activity was significantly associated with the enhancement of the cGAS-STING pathway, interferon response, and inflammatory response. Single-cell analysis confirmed that tumors with high APOBEC3 expression had richer immune cell infiltration, and the activities of four functional modules of the cGAS-STING pathway (cGAS-STING, NF-κB, interferon stimulation, and antigen presentation) were significantly upregulated. In the immunotherapy cohort, patients with high APOBEC3 expression exhibited higher expression of immune checkpoint molecules, and their treatment response rates were significantly superior to those in the low-expression group. Conclusions: APOBEC exhibits distinct driving mechanisms in HNSCC depending on HPV status. Its activity is closely related to cGAS-STING pathway activation, enhanced immune infiltration, and improved immunotherapy efficacy, suggesting potential predictive and therapeutic value.