BackgroundImmunotherapy has introduced new breakthroughs in improving the survival of head and neck squamous cell carcinoma (HNSCC) patients, yet drug resistance remains a critical challenge. Developing personalized treatment strategies based on the molecular heterogeneity of HNSCC is essential to enhance therapeutic efficacy and prognosis.MethodsWe integrated four HNSCC datasets (TCGA-HNSCC, GSE27020, GSE41613, and GSE65858) from TCGA and GEO databases. Using 10 multi-omics consensus clustering algorithms via the MOVICS package, we identified two molecular subtypes (CS1 and CS2) and validated their stability. A machine learning-driven prognostic signature was constructed by combining 101 algorithms, ultimately selecting 30 prognosis-related genes (PRGs) with the Elastic Net model. This signature was further linked to immune infiltration, functional pathways, and therapeutic sensitivity.ResultsCS1 exhibited superior survival outcomes in both TCGA and META-HNSCC cohorts. The PRG-based signature stratified patients into low- and high-risk groups, with the low-risk group showing prolonged survival, enhanced immune cell infiltration (B cells, T cells, monocytes), and activated immune functions (cytolytic activity, T cell co-stimulation). High-risk patients were more sensitive to radiotherapy and chemotherapy (e.g., Cisplatin, 5-Fluorouracil), while low-risk patients responded better to immunotherapy and targeted therapies.ConclusionOur study delineates two molecular subtypes of HNSCC and establishes a robust prognostic model using multi-omics data and machine learning. These findings provide a framework for personalized treatment selection, offering clinical insights to optimize therapeutic strategies for HNSCC patients.