Cancer immunotherapy has revolutionized oncology by harnessing the immune system to recognize and destroy malignant cells. Immune checkpoint inhibitors targeting PD-1, PD-L1, and CTLA-4 have produced durable responses in many cancers, yet a large fraction of patients remain resistant. A major reason for this resistance is that tumors suppress not only T-cell immunity but also innate immune surveillance, particularly natural killer (NK) cell activity. One of the most important inhibitory pathways controlling NK cells and cytotoxic T lymphocytes is mediated by the immune checkpoint receptor NKG2A. Monoclonal antibodies targeting NKG2A represent a new class of immunotherapeutic agents designed to restore both innate and adaptive anti-tumor immunity. Biological Role of NKG2A in Immune Regulation NKG2A (Natural Killer Group 2A, gene name KLRC1) is a member of the C-type lectin receptor family and is predominantly expressed on natural killer (NK) cells and subsets of cytotoxic CD8⁺ T lymphocytes. NKG2A forms a heterodimer with CD94, creating a receptor complex that recognizes the non-classical MHC class I molecule HLA-E. Unlike classical MHC class I molecules (HLA-A, -B, and -C), HLA-E presents a restricted set of peptides, mainly derived from the signal sequences of other MHC class I molecules, serving as a sensor of overall MHC class I expression. The NKG2A/CD94–HLA-E axis functions as a dominant inhibitory immune checkpoint. When HLA-E on a target cell engages NKG2A on NK or CD8⁺ T cells, immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in the cytoplasmic tail of NKG2A become phosphorylated, leading to recruitment of phosphatases such as SHP-1 and SHP-2. These enzymes suppress activating signaling pathways, including those mediated by DAP12, CD3ζ, and ZAP-70, resulting in inhibition of cytotoxic granule release, cytokine production, and immune synapse formation. Physiologically, this system prevents autoreactivity and protects healthy cells from immunemediated damage. However, tumors frequently hijack this pathway to suppress anti-tumor immunity.
