CISH locus-specific integrated IL-15-armored CAR-NK cells

CISH locus-specific integrated IL-15-armored CAR-NK cells are a novel non-viral, genome-edited CAR-NK cell therapy designed to enhance anti-tumor efficacy, particularly against solid tumors like hepatocellular carcinoma (HCC). This therapy utilizes a mini-circular single-stranded DNA (mcssDNA)-based CRISPR/Cas9 technology to achieve site-specific integration of a GPC3-targeting, IL-15-armored CAR into the CISH locus of primary human NK cells. The CISH gene is knocked out to overcome the immunosuppressive tumor microenvironment and prevent NK cell dysfunction, leading to enhanced proliferation, IFN-γ secretion, and cytotoxicity. The integration of IL-15 further boosts the functional persistence of these CAR-NK cells. This approach aims to provide a robust and clinically translatable platform for CAR-NK therapy in solid tumors.