HLA-E is a non-classical MHC class I molecule that serves as a critical immune checkpoint regulator, primarily functioning through interactions with NK cell receptors. HLA-E presents both self-peptides (particularly HLA class Ia leader peptides like VL9) and pathogen-derived peptides to the inhibitory CD94/NKG2A receptor complex on NK cells and CD8+ T cells, thereby suppressing their cytotoxic activity 123. This mechanism enables immune evasion in cancer, as circulating tumor cells exploit the HLA-E:CD94-NKG2A checkpoint to escape NK cell surveillance and facilitate metastasis 1. HLA-E also mediates antigen-specific NK cell memory responses against pathogens like HIV and influenza through the activating NKG2C receptor 4. Unlike classical MHC class I molecules, HLA-E exhibits distinctive intracellular trafficking patterns, being largely retained in the endoplasmic reticulum due to limited high-affinity peptide availability and rapid internalization once surface-expressed 5. Therapeutically, targeting HLA-E represents a promising immunotherapy approach, as blocking HLA-E interactions or disrupting its peptide processing through ERAP inhibition can restore NK cell and CD8+ T cell cytotoxicity against tumors 67. HLA-E's virtual monomorphism and resistance to HIV-mediated downregulation make it an attractive target for vaccine development, particularly for tuberculosis 8.