mutations promote an immunosuppressive tumor microenvironment via to confer immune evasion in head and neck cancer.

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy; however, their efficacy in head and neck cancer (HNC) remains limited, with only a minority of patients achieving durable responses. Understanding the molecular mechanisms underlying ICI resistance in HNC is therefore crucial. We conducted an integrative analysis of genomic, transcriptomic, and clinical data from 139 ICI-treated HNC patients (MSKCC cohort) and 502 treatment-naïve HNC cases (TCGA cohort). mutation status, tumor mutational burden (TMB), neoantigen load, immune cell infiltration (via CIBERSORT), and immune-related gene expression were evaluated. Gene set enrichment analysis (GSEA) was performed to identify dysregulated pathways. Survival outcomes were assessed using Kaplan-Meier analysis and Cox regression, with statistical significance defined as < 0.05. Patients harboring mutations exhibited significantly poorer outcomes following ICI therapy, with shorter median overall survival [OS: 5.0 11.0 months, hazard ratio (HR) = 3.22, 95%CI: 1.26-8.19, = 0.011] compared to wild-type counterparts. Multivariate analysis confirmed mutation as an independent predictor of poor OS in ICI-treated patients (HR = 4.78, 95%CI: 1.70-13.43, = 0.003). In contrast, mutations showed no prognostic significance in the treatment-naïve TCGA-HNC cohort ( = 0.26), confirming their role as a predictive (not prognostic) biomarker for ICI response. Interestingly, despite exhibiting higher TMB and neoantigen levels, -mutant patients showed inferior survival, underscoring the context-dependent limitations of TMB as a predictive biomarker. Mechanistically, -mutant tumors displayed an immunosuppressive tumor microenvironment characterized by diminished CD8 T cell infiltration, attenuated interferon-γ signaling, and downregulation of immune-related genes (, , , ). GSEA revealed enrichment of pathway activity in -mutant tumors, which suppressed antigen presentation and T cell activation pathways. mutations drive ICI resistance in HNC by promoting an immunosuppressive TME via -mediated transcriptional reprogramming, impairing antigen presentation and T cell function. Incorporating status into biomarker panels may improve patient stratification and guide combinatorial therapies targeting both immune evasion and oncogenic pathways.