Multi-Omics Biomarkers in Head and Neck Squamous Cell Carcinoma: Biological Insights and Clinical Translation: A Narrative Review

Head and neck squamous cell carcinoma (HNSCC) continues to be an important health problem worldwide, with high morbidity and mortality and considerable biological variability among tumors. Although clinicopathological features remain essential in clinical practice, they do not fully explain differences in tumor behavior or treatment response. The growing availability of molecular data has therefore increased interest in multi-omics strategies for HNSCC. Genomic, transcriptomic, epigenomic, proteomic, and metabolomic analyses provide different, but complementary, views of tumor biology. Genomic alterations, including recurrent changes in TP53 and PIK3CA, help define the molecular landscape of HNSCC, while transcriptomic biomarkers such as PD-L1 expression and epithelial–mesenchymal transition (EMT)-related signatures provide insights into tumor–microenvironment interactions, immune evasion, and treatment resistance. Epigenetic alterations further regulate gene expression, whereas proteomic and metabolomic biomarkers provide information more closely related to cellular function, metabolic reprogramming, and disease progression. More recently, single-cell and spatial approaches have allowed tumors to be studied according to their cellular composition and tissue organization. Artificial intelligence and machine learning are also being explored to combine these large datasets and identify biomarkers related to prognosis or therapeutic response. This review critically discusses the principal multi-omics biomarkers investigated in HNSCC, including biomarkers associated with genomic instability, immune regulation, EMT, and metabolic reprogramming, highlighting their potential clinical applications and the current barriers limiting their incorporation into routine practice.