Head and neck squamous cell carcinoma (HNSC) is a highly aggressive malignancy with poor prognosis, necessitating the identification of novel biomarkers for improved diagnosis and treatment. The exosome complex (EXOSC) family plays a crucial role in RNA metabolism, but its significance in HNSC remains poorly understood. We performed a comprehensive multi-omics analysis integrating data from TCGA, GEO, CPTAC, and the Human Protein Atlas to investigate the expression, prognostic value, and immune relevance of EXOSC genes in HNSC. We conducted differential expression analysis, survival analysis (OS, DSS, PFI), ROC curve evaluation, and clinicopathological correlation studies. Genetic alterations were examined using cBioPortal. Gene co-expression and enrichment analyses were used to elucidate potential molecular functions, and a protein–protein interaction (PPI) network was constructed via GeneMANIA. Immune infiltration, immune checkpoint correlations, and RNA modification associations were assessed using ssGSEA, Spearman correlation, and RNA modification databases. Experimental validation was performed by qRT-PCR in HNSC and normal cell lines. All EXOSC family members were significantly upregulated in HNSC tissues and cell lines. ROC analysis demonstrated favorable diagnostic potential, particularly for EXOSC2 (AUC = 0.910). Elevated expression of EXOSC2, EXOSC3, EXOSC8, and EXOSC9 was significantly associated with poor OS, DSS, and PFI. High expression of EXOSC2, EXOSC4, EXOSC5, and EXOSC9 correlated with advanced clinical stage, lymphovascular invasion, and poor therapeutic outcomes. cBioPortal analysis revealed EXOSC4 had the highest genetic alteration frequency (8%), primarily due to amplification. Immune infiltration analysis showed EXOSC gene expression was significantly correlated with various immune cell populations and immune checkpoint molecules, especially EXOSC3, EXOSC9, and EXOSC10. Functional enrichment and PPI network analyses indicated that EXOSC family genes participate in RNA metabolism, exoribonuclease activity, and immune-related pathways. A prognostic risk model based on EXOSC co-expressed genes demonstrated strong predictive performance for patient survival. Our study reveals that EXOSC family genes are significantly dysregulated in HNSC and are associated with tumor progression, prognosis, immune microenvironment modulation, and RNA modification. These findings highlight the potential of EXOSC members as novel diagnostic and prognostic biomarkers and suggest their relevance as therapeutic targets in HNSC.
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