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

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.