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Peer-reviewedCC BY 4.0Frontiers in Immunology

The HLA-E–NKG2A axis in breast cancer: an emerging NK-cell checkpoint and therapeutic target

  • Lvzhu Li1
  • Xiaoxu Han1
  • Lu Lu2
  • Kuan Liu3
  • Yongle Li3
  • Lei Su4
4 affiliations
  1. 1Department of Breast Surgery, Affiliated Hospital of Hebei University
  2. 2Department of Anesthesiology, Affiliated Hospital of Hebei University
  3. 3Department of Radiation Oncology, Affiliated Hospital of Hebei University
  4. 4Department of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Hebei University
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Abstract

Immune-checkpoint blockade has improved outcomes in triple-negative breast cancer (TNBC), but resistance remains common. Natural killer (NK) cells provide complementary surveillance when classical major histocompatibility complex class I (MHC-I) expression is lost or heterogeneous. HLA-E can inhibit NK cells and subsets of CD8+ T cells through CD94/NKG2A, but can also engage activating CD94/NKG2C. In breast cancer, HLA-E associations depend on classical MHC-I status, while spatial TNBC studies link MHC-I heterogeneity to NKG2A-mediated resistance in experimental models. Evidence varies by subtype and remains predominantly translational; clinical efficacy of NKG2A blockade has not been established, including in the small MIMOSA trial of HER2-positive disease. This Mini Review evaluates breast cancer-specific and cross-tumor evidence, the NKG2A/NKG2C balance, therapeutic combinations, and practical biomarker development. We propose prospective assessment of tumor-cell surface HLA-E, regional MHC-I status, NKG2A-positive effectors, activating-receptor balance, and spatial proximity rather than HLA-E positivity alone.

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Cite

BibTeXRIS
BibTeX
@article{li2026hlaenkg2a,
  title = {{The HLA-E–NKG2A axis in breast cancer: an emerging NK-cell checkpoint and therapeutic target}},
  author = {Lvzhu Li and Xiaoxu Han and Lu Lu and Kuan Liu and Yongle Li and Lei Su},
  journal = {Frontiers in Immunology},
  year = {2026},
  month = oct,
  doi = {10.3389/fimmu.2026.2001812},
  url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.2001812/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - The HLA-E–NKG2A axis in breast cancer: an emerging NK-cell checkpoint and therapeutic target
AU  - Lvzhu Li
AU  - Xiaoxu Han
AU  - Lu Lu
AU  - Kuan Liu
AU  - Yongle Li
AU  - Lei Su
PY  - 2026
DA  - 2026/10/28
JO  - Frontiers in Immunology
DO  - 10.3389/fimmu.2026.2001812
UR  - https://www.frontiersin.org/articles/10.3389/fimmu.2026.2001812/full
AB  - Immune-checkpoint blockade has improved outcomes in triple-negative breast cancer (TNBC), but resistance remains common. Natural killer (NK) cells provide complementary surveillance when classical major histocompatibility complex class I (MHC-I) expression is lost or heterogeneous. HLA-E can inhibit NK cells and subsets of CD8+ T cells through CD94/NKG2A, but can also engage activating CD94/NKG2C. In breast cancer, HLA-E associations depend on classical MHC-I status, while spatial TNBC studies link MHC-I heterogeneity to NKG2A-mediated resistance in experimental models. Evidence varies by subtype and remains predominantly translational; clinical efficacy of NKG2A blockade has not been established, including in the small MIMOSA trial of HER2-positive disease. This Mini Review evaluates breast cancer-specific and cross-tumor evidence, the NKG2A/NKG2C balance, therapeutic combinations, and practical biomarker development. We propose prospective assessment of tumor-cell surface HLA-E, regional MHC-I status, NKG2A-positive effectors, activating-receptor balance, and spatial proximity rather than HLA-E positivity alone.
SN  - 1664-3224
ER  -