Objective: To examine the impact of viral infection and carcinogens on the head and neck squamous cell carcinoma (HNSCC) tumor immune microenvironment (TIME) and assess whether the immune signature offers valuable clinical insights for immunotherapy. Methods: By integrating the scRNA-seq data of tumor-infiltrating leukocytes (TILs) from both HPV-negative (HPV ^-) and HPV-positive (HPV ⁺) HNSCC patients from TCGA cohort, a comprehensive map of TIME in HNSCC was created. Results and Conclusions: TILs exhibited distinct cellular composition and gene expression between HPV ^- and HPV ⁺ HNSCC. The remodeling of myeloid cells indicated that activated dendritic cells possess migratory potential in HNSCC. C1QC ⁺ tumor-associated macrophages (TAMs) displayed an M2 signature in HPV ^- HNSCC, which may result from the regulation of NR1H3. Further analysis of T cells demonstrated that increased T follicular helper (Tfh) infiltration predicted improved survival in HPV ⁺ HNSCC. These data point to an activation-dependent exhaustion expression program, particularly for TIGIT in GZMK ⁺ exhausted T cells in HPV ^- HNSCC. And more robust CCL signaling in HPV ⁺ HNSCC provides insights into the molecular basis for precision medicine.