Integrative analysis of aging-related immune parameters reveals prognostic and immunotherapeutic implications in head and neck squamous cell carcinoma

• Aging-related immune parameters predict prognosis in HNSCC. • Immune aging is associated with CD8+ T cell exhaustion. • Naïve CD8+ T cells are a prognostic factor for HNSCC treated with ICIs. Head and neck squamous cell carcinoma (HNSCC) predominantly affects older individuals; however, the prognostic significance of aging-related immune parameters in HNSCC remains unclear. We retrospectively analyzed peripheral blood samples from 77 pretreatment patients and 36 patients treated with immune checkpoint inhibitors (ICIs). Five aging-related immune parameters, chronological age, the percentage of naïve CD8 + T cells, CD4/CD8 ratio, C-reactive protein (CRP), and the percentage of regulatory T cells (Treg), were evaluated. Their associations with exhaustion markers on CD8 + T cells and clinical outcomes were analyzed. Prognostic prediction and risk stratification models were constructed using least absolute shrinkage and selection operator (LASSO) regression analysis and recursive partitioning analysis (RPA). Several aging-related immune parameters were associated with prognosis in pretreatment HNSCC patients; however, CRP was the only independent prognostic factor for progression-free survival. Notably, the proportion of naïve CD8+ T cells showed a positive correlation with the frequency of TIM-3+ CD8+ T cells, suggesting preserved immune responsiveness rather than advanced immune aging. Integrated prognostic models constructed using LASSO and RPA enabled more accurate prediction of progression-free and overall survival than individual parameters alone. In the ICI-treated cohort, the proportion of naïve CD8+ T cells emerged as the most robust prognostic parameter in patients treated with ICIs. Immune aging represents a complex immunological state interwoven with multiple factors and reflects not only tumor-bearing conditions but also clinical outcomes in patients with HNSCC. The development of new therapeutic approaches capable of modulating or reversing immune aging will be required.