Mass General Brigham and Broad Institute researchers deployed comprehensive CRISPR screening across the T cell lifecycle to discover gene knockouts enhancing CAR T cell proliferation, persistence, and anti-myeloma activity. Key findings indicate that deletion of cell cycle regulator CDKN1B significantly improves in vivo CAR T efficacy, a discovery enabled through in vitro culture and subsequent mouse models. These insights could streamline optimization of CAR T cell immunotherapies, extending their durability and effectiveness against multiple myeloma and potentially other cancers.