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, thus playing a crucial role in the immunosuppressive tumor microenvironment and immune regulation [1].

Genetic modification of Klrc1 has shown promising results. KLRC1 knockout in ex vivo expanded human NK cells reduced the frequency of NKG2A+ cells. In vitro, KLRC1 KO NK cells exhibited significantly higher cytotoxicity against HLA-E+ solid tumor cell lines compared to wild-type NK cells, and in vivo, adoptive transfer of human KLRC1 KO NK cells significantly delayed tumor progression and increased survival in a xenogeneic mouse model of HLA-E+ metastatic breast cancer [1]. Similarly, CRISPR-mediated KLRC1 gene editing in CD33-directed chimeric antigen receptor natural killer cells improved their antileukemic killing activity against acute myeloid leukemia cell lines and primary blasts in vitro and in vivo [2]. Additionally, CRISPR-Cas9 disruption of the KLRC1 gene in NK cells isolated from human peripheral blood, combined with non-viral insertion of a GD2-targeting chimeric antigen receptor, led to the generation of potent allogeneic cell therapies against HLA-E+ solid tumors [3].

In conclusion, Klrc1 is essential for regulating NK cell function through the NKG2A/HLA-E axis. Studies using Klrc1 knockout models have demonstrated its significant impact on enhancing NK cell-mediated antitumor activity, providing potential strategies for developing immunotherapies against solid tumors and leukemia [1,2,3].