Translational cancer research · 2026
Targeting the MICA/B-NKG2D axis in cancer: from molecular structure to immunotherapeutic strategies-a narrative review.
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Zheng Yuwei, Ding Wanyi, Chen Bingbing, Geng Caizheng, Li Xiaowei
Аннотация
BACKGROUND AND OBJECTIVE: The interaction between major histocompatibility complex class I chain-related proteins A and B (MICA/B) and the activating receptor natural killer group 2 member D (NKG2D) represents a critical axis in anti-tumor immunity. This pathway plays a central role in the recognition and elimination of stressed or transformed cells by natural killer (NK) cells and CD8+ T cells. However, tumors frequently develop diverse mechanisms to disrupt this axis, leading to immune escape. This review aims to provide a comprehensive overview of the molecular structure, regulatory mechanisms, and therapeutic targeting strategies of the MICA/B-NKG2D pathway in cancer.
METHODS: A systematic literature search is conducted using PubMed databases to identify recent studies related to the structure, regulation, and therapeutic targeting of the MICA/B-NKG2D axis. Relevant experimental and clinical studies are analyzed, and a narrative review is performed to synthesize current knowledge and emerging insights.
KEY CONTENT AND FINDINGS: This review first summarizes the molecular structure of MICA/B and the structural basis of their interaction with NKG2D, highlighting the functional impact of polymorphisms. It then outlines the multi-layered regulatory mechanisms governing MICA/B expression, including transcriptional, epigenetic, and post-translational regulation, with particular emphasis on proteolytic shedding mediated by a disintegrin and metalloproteinases (ADAMs) and matrix metalloproteinases (MMPs). The immunosuppressive role of soluble MICA/B in downregulating NKG2D expression and inducing effector cell dysfunction is discussed in detail. Furthermore, the role of the tumor microenvironment (TME) in modulating this axis through stromal cells, immune cells, metabolic stress, and extracellular vesicles is comprehensively analyzed. Finally, emerging therapeutic strategies targeting this pathway-including shedding inhibitors, expression enhancers, cellular therapies, and combination approaches-are critically evaluated.
CONCLUSIONS: The MICA/B-NKG2D axis is a key regulator of tumor immune surveillance and a major target of tumor immune evasion. Its dysregulation is driven by complex and multilayered mechanisms involving tumor-intrinsic alterations and the TME. Therapeutic strategies aimed at restoring this axis show promising clinical potential, although challenges such as ligand polymorphism, soluble ligand interference, and on-target toxicity remain. A deeper understanding of the regulatory network and rational design of combination therapies will be essential for translating this pathway into effective cancer immunotherapies.
METHODS: A systematic literature search is conducted using PubMed databases to identify recent studies related to the structure, regulation, and therapeutic targeting of the MICA/B-NKG2D axis. Relevant experimental and clinical studies are analyzed, and a narrative review is performed to synthesize current knowledge and emerging insights.
KEY CONTENT AND FINDINGS: This review first summarizes the molecular structure of MICA/B and the structural basis of their interaction with NKG2D, highlighting the functional impact of polymorphisms. It then outlines the multi-layered regulatory mechanisms governing MICA/B expression, including transcriptional, epigenetic, and post-translational regulation, with particular emphasis on proteolytic shedding mediated by a disintegrin and metalloproteinases (ADAMs) and matrix metalloproteinases (MMPs). The immunosuppressive role of soluble MICA/B in downregulating NKG2D expression and inducing effector cell dysfunction is discussed in detail. Furthermore, the role of the tumor microenvironment (TME) in modulating this axis through stromal cells, immune cells, metabolic stress, and extracellular vesicles is comprehensively analyzed. Finally, emerging therapeutic strategies targeting this pathway-including shedding inhibitors, expression enhancers, cellular therapies, and combination approaches-are critically evaluated.
CONCLUSIONS: The MICA/B-NKG2D axis is a key regulator of tumor immune surveillance and a major target of tumor immune evasion. Its dysregulation is driven by complex and multilayered mechanisms involving tumor-intrinsic alterations and the TME. Therapeutic strategies aimed at restoring this axis show promising clinical potential, although challenges such as ligand polymorphism, soluble ligand interference, and on-target toxicity remain. A deeper understanding of the regulatory network and rational design of combination therapies will be essential for translating this pathway into effective cancer immunotherapies.