Base Editing of TIGIT Reprograms CD155 Signaling in NK Cells for Enhanced Cancer Immunotherapy

NK cells hold great promise for cancer immunotherapy owing to their intrinsic capacity to recognize and eliminate malignant cells. Nevertheless, broad clinical deployment is hindered by poor expansion, refractoriness to genetic modification, and tumor immune-evasion mechanisms. Here, we applied base-editing technology to precisely modify signal transduction in human primary NK cells. We achieved a high editing efficiency of the TIGIT gene (>90%) in peripheral blood-derived NK (TIGIT BE-NK) cells, forcing tumor-derived CD155 to engage CD226 and thereby converting an inhibitory signal into an activating one that amplified NK cell cytotoxicity. TIGIT BE-NK cells specifically targeted the tumor site as demonstrated by droplet digital PCR (ddPCR). Additionally, TIGIT BE-NK cells were validated as safe, with minimal off-target effects. These results underscored the feasibility of base editing directed NK cells, significantly enhancing their therapeutic potential in clinical settings.