Anti-programmed death 1 (PD-1) and epidermal growth factor receptor (EGFR)-based neoadjuvant therapy was confirmed to be effective for the treatment of head and neck squamous cell carcinoma (HNSCC). However, a previous study found that nearly 1/3 of HPV-negative HNSCC experienced no significant reduction or even increase in tumor size.1 Up till now, few studies have demonstrated the clinicopathological patterns of PD-L1+ EGFR+ HNSCC patients. Therefore, single-cell RNA-sequencing (scRNA-seq) analysis was applied in our retrospective study of 1077 HPV-negative HNSCC patients to characterize the immune patterns of the tumor microenvironment (TME) after anti-PD-1 and EGFR-based neoadjuvant therapy. In this study, we identified for the first time that most PD-L1+ EGFR+ HNSCC patients were in an advanced clinical stage and suffered lymph node metastasis. HPV-negative HNSCC patients experienced a significant reduction of tumor size after receiving 1 course of anti-PD-1 and EGFR-based neoadjuvant therapy. Meanwhile, PD-L1+ EGFR+ HNSCC patients have stronger invasive ability. The CXCL11/CXCR3 pair in PD-L1+ EGFR+ HNSCC cells contributed to the construction of an immunosuppressive TME by recruiting plasmacytoid dendritic cells, regulatory T cells, dendritic cells and CD8+ T cells. CD73, OX40, and TIM-3 are potential targets for immunotherapy sensitization in HPV-negative HNSCC. Our finding provides an immunotherapeutic sensitization strategy for PD-L1+ EGFR+ HNSCC.