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Biomolecules
Volume 16
Issue 1
10.3390/biom16010047
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Review

Association Between Amino Acid Polymorphisms in MICA and MICA-NKG2D Interaction Affinity: Implications and Significance for Tumor Immunity

by
Chuyu Xiao
1,†,
Wang Wang
1,†,
Yangyang Zhang
1,
Ting Huang
2,
Chunjing Chen
3,
Biyuan Liu
1,
Chang Liu
4,
Yingying Yang
1,
Fangguo Lu
3,* and
Quan Zhu
1,*
1
Department of Immunology, School of Medicine, Hunan University of Chinese Medicine, Changsha 410208, China
2
Department of Pathology, School of Medicine, Hunan University of Chinese Medicine, Changsha 410208, China
3
Department of Pathogenic Biology, School of Medicine, Hunan University of Chinese Medicine, Changsha 410208, China
4
Department of Histology and Embryology, School of Medicine, Hunan University of Chinese Medicine, Changsha 410208, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to the work.
Biomolecules 2026, 16(1), 47; https://doi.org/10.3390/biom16010047 (registering DOI)
Submission received: 9 November 2025 / Revised: 19 December 2025 / Accepted: 27 December 2025 / Published: 28 December 2025
(This article belongs to the Special Issue Signal Transduction and Pathway Regulation in Cancer)
Review Reports Versions Notes

Abstract

Major histocompatibility complex class I-like related gene A (MICA) is the most polymorphic non-classical HLA gene. MICA proteins are expressed at low levels on the surface of normal cells but are highly expressed on the surface of tumor cells. Its most important biological function is to bind to activating receptors on the surface of natural killer (NK) cells or CD8+ T cells, then activate these immune cells to exert immune killing effects. Multiple studies have shown that the amino acids at specific loci in the MICA molecule can significantly affect its binding ability to NKG2D. The binding strength of MICA-NKG2D significantly affects the anti-tumor effect of NK cells in the body and the prognosis of many tumor patients. However, the strong MICA-NKG2D interaction can trigger negative feedback against this immune response by down-regulating the expression of NKG2D or generating soluble MICA, weakening the overly intense immune response. Therefore, simply evaluating the intensity of the anti-tumor immune response from the perspective of the amino acid polymorphism of MICA affecting its binding ability to NKG2D also has limitations. We review the effects of MICA amino acid polymorphism on the affinity of the NKG2D signal pathway and analyze in detail the specific role of MICA amino acid polymorphism in tumor immunity. The study provides a reference for understanding the mechanism of anti-tumor immune response by NK cells or other immune cells, as well as a theoretical basis for considering the MICA-NKG2D signal axis for anti-tumor immune therapy in future clinical practice.
Keywords: MICA; polymorphism; tumor immunity; NK cells MICA; polymorphism; tumor immunity; NK cells

Share and Cite

MDPI and ACS Style

Xiao, C.; Wang, W.; Zhang, Y.; Huang, T.; Chen, C.; Liu, B.; Liu, C.; Yang, Y.; Lu, F.; Zhu, Q. Association Between Amino Acid Polymorphisms in MICA and MICA-NKG2D Interaction Affinity: Implications and Significance for Tumor Immunity. Biomolecules 2026, 16, 47. https://doi.org/10.3390/biom16010047

AMA Style

Xiao C, Wang W, Zhang Y, Huang T, Chen C, Liu B, Liu C, Yang Y, Lu F, Zhu Q. Association Between Amino Acid Polymorphisms in MICA and MICA-NKG2D Interaction Affinity: Implications and Significance for Tumor Immunity. Biomolecules. 2026; 16(1):47. https://doi.org/10.3390/biom16010047

Chicago/Turabian Style

Xiao, Chuyu, Wang Wang, Yangyang Zhang, Ting Huang, Chunjing Chen, Biyuan Liu, Chang Liu, Yingying Yang, Fangguo Lu, and Quan Zhu. 2026. "Association Between Amino Acid Polymorphisms in MICA and MICA-NKG2D Interaction Affinity: Implications and Significance for Tumor Immunity" Biomolecules 16, no. 1: 47. https://doi.org/10.3390/biom16010047

APA Style

Xiao, C., Wang, W., Zhang, Y., Huang, T., Chen, C., Liu, B., Liu, C., Yang, Y., Lu, F., & Zhu, Q. (2026). Association Between Amino Acid Polymorphisms in MICA and MICA-NKG2D Interaction Affinity: Implications and Significance for Tumor Immunity. Biomolecules, 16(1), 47. https://doi.org/10.3390/biom16010047

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