USP33 as a potential prognostic and immunological biomarker in head and neck squamous cell carcinoma: a TCGA-based bioinformatic analysis

Abstract Background Head and neck squamous cell carcinoma (HNSCC) is a prevalent and aggressive malignancy with limited prognostic markers. Ubiquitin-specific peptidase 33 (USP33) has emerged as a potential modulator of tumor biology and immune responses, although its role in HNSCC remains incompletely understood. Objective To investigate the expression, exploratory prognostic associations, and immunological associations of USP33 in HNSCC using bioinformatic approaches. Methods This study is an in silico bioinformatic analysis of transcriptomic RNA-seq data from The Cancer Genome Atlas (TCGA-HNSC). USP33 expression in tumor and normal tissues and across clinicopathological subgroups was evaluated. Immune infiltration was estimated using TIMER 2.0 and CIBERSORTx, and overall survival was assessed using Kaplan–Meier analysis. Functional enrichment and protein–protein interaction analyses were performed using KEGG, GO, STRING, and DisGeNET databases. Results USP33 was significantly overexpressed in HNSCC, particularly in HPV-positive tumors, and inversely correlated with TP53 mutation status. Its expression increased with advanced tumor stage and grade. USP33 levels showed a positive association with M2 macrophage infiltration, suggesting an immunomodulatory role. Despite its association with aggressive clinicopathological features, higher USP33 expression showed a context-dependent association with improved overall survival, particularly in HPV-positive patients. Enrichment analysis indicated involvement in apoptosis, protein degradation, and immune signaling pathways. Conclusion USP33 acts as a context-dependent biomarker in HNSCC, reflecting both tumor aggressiveness and immune landscape. Its dual association with macrophage polarization and favorable survival outcomes, especially in HPV-related tumors, suggests that USP33 may serve as a context-dependent candidate biomarker, warranting further validation.