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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月25日

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  • Parsa Alijanizadeh,
  • Mahshid Shahmoradi,
  • Amirhossein Kamroo,
  • Tara Shahmoradi,
  • Fatemeh Tajafrooz,
  • Pegah khodaee,
  • Niloufar Yazdanpanah,
  • Kiarash Saleki,
  • Nima Rezaei

摘要

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.