From Radiation to Immune Response: A Systematic Review of Systemic Immunomodulation in Squamous Cell Head and Neck Cancer

Head and neck squamous cell carcinoma (HNSCC) is frequently treated with radiotherapy (RT), often combined with chemotherapy. Beyond local tumor control, RT induces systemic immunomodulatory effects. This systematic review evaluates alterations in peripheral immune cell subpopulations and circulating biomarkers in HNSCC patients undergoing RT with or without chemotherapy. METHODS: A systematic search across five databases identified 12 eligible studies. Inclusion criteria encompassed adult patients with HNSCC treated with external beam RT and analysis of immune parameters in peripheral blood. The review protocol was registered in the Prospective Register of Systematic Reviews (PROSPERO, registration number CRD42021283028). RESULTS: RT induced lymphopenia, with consistent reductions in T, B, and dendritic cells, and increases in regulatory T cells (Tregs). Altered expression of immune activation markers (such as CD69 and HLA-DR) and exhaustion markers (such as PD-1 and CTLA-4) was noted. Gene expression of FDXR, GADD45, and others demonstrated sustained modulation post-RT. Changes in cytokines, adhesion molecules (CX3CR1, CD11a), and immune checkpoint proteins (PD-L1) were associated with treatment response and toxicity. Baseline immune profiles correlated with the risk of acute toxicity. CONCLUSION: RT, either alone or in combined with chemotherapy, significantly alters systemic immunity in HNSCC. Immunophenotyping and peripheral biomarkers show prognostic potential, supporting their integration into personalized treatment strategies. However, standardized, large-scale longitudinal studies are warranted.