Base Editing of TIGIT Reprograms CD155 Signaling in Natural Killer Cells to Enhance Cancer Immunotherapy Efficacy

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 NK-cell properties like poor expansion and refractoriness to genetic modification, as well as by tumor immune-evasion mechanisms. In this study, we applied base-editing technology to precisely modify signal transduction in primary human NK cells, which achieved a high editing efficiency of the T-cell immunoreceptor with Ig and ITIM domains (TIGIT) gene (>90%) in peripheral blood-derived NK (TIGIT BE-NK) cells. TIGIT editing forced tumor-derived CD155 to engage CD226 and thereby converted an inhibitory signal into an activating one that amplified NK-cell cytotoxicity. TIGIT BE-NK cells specifically targeted cancer cells across multiple tumor types and were validated as safe, with minimal off-target effects. Cryopreserved TIGIT BE-NK cells exhibited similar antitumor activity as fresh TIGIT BE-NK cells, supporting their potential as an "off-the-shelf" therapy. Combining TIGIT BE-NK cells and IL2 further improved antitumor immunity. Together, these results underscore the feasibility of using base editing to modify NK cells and significantly enhance their therapeutic potential for treating patients with cancer. Significance: Modifying a single base within the TIGIT gene in NK cells switches inhibitory signaling to an activating axis that enhances antitumor immunity, supporting base editing of immune cells as an immunotherapeutic strategy.