Klrc1, which encodes the NK cell inhibitory receptor NKG2A, is a key gene in the immune system. NKG2A specifically binds to HLA-E, a non-classical HLA class I molecule, leading to the transmission of inhibitory signals that strongly impair NK cell function [1]. This interaction is part of the immunosuppressive tumor microenvironment (TME) and immune-related pathways [1].

Gene knockout studies have shown great value in understanding Klrc1's role. KLRC1 knockout in ex vivo expanded human NK cells reduced the frequency of NKG2A+ cells, and in vitro, KLRC1 KO NK cells exhibited significantly higher cytotoxicity against HLA-E+ solid tumor cell lines compared to wild-type NK cells. In vivo, adoptive transfer of human KLRC1 KO NK cells significantly delayed tumor progression in a xenogeneic mouse model of HLA-E+ metastatic breast cancer [1]. Similar positive effects on antitumor activity were seen when using CRISPR-mediated KLRC1 gene editing in CD33-directed chimeric antigen receptor natural killer cells against acute myeloid leukemia [2]. Also, in the context of keloids, the NKG2A/CD94 complex (encoded by Klrc1) was specifically upregulated, potentially contributing to the reduction of cytotoxic CD8+ T cells in scar tissue [3].

In conclusion, Klrc1 plays a crucial role in immune regulation, especially in the inhibition of NK cell-mediated antitumor activity through the NKG2A-HLA-E interaction. Gene knockout models have revealed its significance in tumor-related diseases, suggesting that targeting Klrc1 could be a potential strategy for enhancing antitumor immunity in cancer treatment.