Integrative immune subtyping of HNSCC reveals clinically relevant phenotypes and treatment-associated transitions

Head and neck squamous cell carcinoma (HNSCC) shows marked heterogeneity in clinical behavior, treatment response, and immune contexture. Existing molecular and immune classification systems are often derived from small, homogeneous cohorts and lack integration of multimodal data, limiting clinical relevance. We performed an integrated multi-omics analysis of transcriptomic and genomic data (copy number alterations and single-nucleotide variants) from 1149 tumors across 1102 HNSCC patients spanning multiple treatment settings. Using Similarity Network Fusion (SNF) on immune-related gene profiles, we identified immune subtype clusters (ISCs) and characterized them through mutational, transcriptional, immune cell enrichment, hypoxia, and established molecular subtype analyses. Clinical associations, including progression-free survival, were evaluated in first-line and post-metastatic settings. Four ISCs were defined: ISC1, immune-cold and EMT-enriched; ISC2, immune-activated; ISC3, mixed immune-regulatory with stromal enrichment; and ISC4, immunosuppressed. These subtypes showed distinct clinical outcomes and differential responses to checkpoint inhibitors, chemotherapy, and combination therapies. Analysis of 44 patients with matched pre- and post-treatment tumors revealed dynamic immune-state transitions, with checkpoint inhibition promoting immune activation and chemotherapy enriching immunosuppressive signaling. This study establishes a clinically relevant immune subtyping framework for HNSCC that captures dynamic tumor-immune states linked to treatment response and survival, supporting its utility in guiding immune-based therapies.