Targeting the NKG2D axis in head and neck squamous cell carcinoma: from molecular insights to clinical applications.

Head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer that evades immune surveillance by impairing the NKG2D receptor on natural killer (NK) cells and cytotoxic T lymphocytes. NKG2D recognizes stress-induced ligands (e.g., MICA, MICB, ULBPs) on tumor cells, but HNSCC tumors counteract this by shedding soluble ligands and secreting immunosuppressive cytokines like TGF-β1, reducing NKG2D expression and function. This review explores therapeutic strategies targeting the NKG2D axis to enhance HNSCC treatment. Cytokine therapies, such as IL-2 or IL-15, boost NKG2D-dependent NK cell activation. Monoclonal antibodies targeting MICA/B or ULBPs prevent ligand shedding and induce antibody-dependent cellular cytotoxicity (ADCC). Engineered cell therapies, including NKG2D-based chimeric antigen receptor (CAR)-T and CAR-NK cells, show potent preclinical efficacy against HNSCC. Combining these approaches with EGFR-targeted antibodies (e.g., cetuximab) or checkpoint inhibitors enhances NKG2D-mediated immunity. Despite promising results, challenges persist, including heterogeneous ligand expression, persistent shedding, and the immunosuppressive tumor microenvironment, which limit clinical efficacy. Future directions include multimodal strategies like bispecific NK-cell engagers and integration with chemoradiotherapy to overcome these barriers. By restoring NKG2D-driven immunity, these therapies hold potential to improve outcomes for HNSCC patients, though further research is needed to optimize their clinical translation.