Background <p>Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with poor prognosis, partly due to an immunosuppressive tumor microenvironment. The immune-related gene CCDC86, selectively expressed in hematopoietic and antigen-presenting cells, has not been previously characterized in HNSCC. We aimed to delineate its expression pattern and immunological functions using integrated single-cell transcriptomic analysis.</p> Methods <p>Bulk RNA-sequencing data from The Cancer Genome Atlas (TCGA) and single-cell RNA-sequencing data (GEO: GSE139324) were integrated to assess CCDC86 expression, immune-cell specificity, and associated transcriptional programs in HNSCC. Differential expression, pathway enrichment, transcription factor regulon, and cell–cell communication analyses were conducted between CCDC86-high and CCDC86-low populations. The immune contexture and ligand–receptor interactions of CCDC86-expressing cells were evaluated to infer their roles in tumor–immune modulation. Additionally, qPCR validation following CCDC86 knockdown in FaDu cells was performed to confirm the transcriptional alterations of immune-related genes identified by bioinformatic analysis.</p> Results <p>CCDC86 was predominantly expressed in tumor-infiltrating antigen-presenting cells (APCs), including macrophages and dendritic cells. CCDC86-high APCs exhibited enhanced SPI1- and CEBPA-regulated transcriptional activity, metabolic reprogramming, and altered antigen-presentation signatures.Ligand–receptor network analysis revealed intensified interactions with T cells via both co-stimulatory (CD86–CD28) and checkpoint (PDCD1, CTLA4) pathways, suggesting dual immunomodulatory potential. Functionally, CCDC86-high APCs were associated with increased cytotoxic T-cell infiltration but concurrent T-cell dysfunction, implying that CCDC86 defines a specialized APC state that sustains chronic immune activation yet promotes tolerance within the tumor microenvironment. Additionally, qPCR validation following CCDC86 knockdown in FaDu cells was performed to confirm the transcriptional alterations of immune-related genes identified by bioinformatic analysis.</p> Conclusions <p>CCDC86 acts as a key regulator of immune communication in HNSCC, orchestrating APC–T cell interactions and shaping an immunoregulatory niche. By linking antigen presentation with checkpoint signaling, CCDC86 contributes to immune evasion while maintaining local immune activation. These findings highlight CCDC86 as a promising prognostic biomarker and potential immunotherapeutic target in HNSCC.</p>