KLRC1 encodes NKG2A, an inhibitory C-type lectin receptor expressed on natural killer (NK) cells and CD8+ T cells that recognizes HLA-E, a non-classical MHC class I molecule 1. Upon engagement with HLA-E, KLRC1 mediates inhibitory signaling that suppresses cytotoxic function and promotes immune cell exhaustion 2. In SARS-CoV-2 infection, KLRC1 recognition of HLA-E complexed with viral peptides on lung epithelial cells dampens antiviral immune surveillance and contributes to NK cell and CD8+ T cell exhaustion 3. In cancer contexts, KLRC1 expression on CD8+ T cells correlates with exhaustion in multiple malignancies including gastric cancer, breast cancer, acral melanoma, and acute myeloid leukemia, and represents an alternative immune checkpoint axis independent of classical PD-1/PD-L1 pathways 2456. Clinically, KLRC1 disruption via CRISPR/Cas9 in CAR-NK cells enhances anti-tumor killing by overcoming HLA-E-mediated inhibition, demonstrating therapeutic potential 17. Additionally, tri-specific nano-antibodies targeting KLRC1 alongside PDL1 and 4-1BB effectively activate NK and T cell antitumor responses 8. These findings establish KLRC1 as a clinically relevant immune checkpoint warranting therapeutic targeting, particularly in HLA-E-expressing tumors.