Targeting the Nkg2d Axis in Head and Neck Squamous Cell Carcinoma: From Molecular Insights to Clinical Applications Publisher



Alijanizadeh P ; Shahmoradi M ; Kamroo A ; Shahmoradi T ; Tajafrooz F ; Khodaee P ; Yazdanpanah N ; Saleki K ; Rezaei N
Source: Cancer Cell International Published:2026

Abstract

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. © The Author(s) 2026.