Customized genetic engineering has opened a new frontier for enhancing CAR T cells, the “living drugs” used to fight cancer. While this therapy is a milestone in modern medicine, its effectiveness is often limited because the engineered T cells become exhausted, particularly when treating blood cancers.
To address this, scientists from CeMM and the Medical University of Vienna created CELLFIE, a platform combining CAR T cell engineering with high-content CRISPR screening to systematically boost cell function. Published in Nature, the platform allows researchers to test the effect of knocking out every human gene. A key discovery was that knocking out the RHOG gene made CAR T cells substantially more potent against leukemia in preclinical models. This suggests that genes important for natural immunity can paradoxically weaken genetically engineered CAR T cells.
Furthermore, combining the knockout of RHOG with a knockout of the FAS gene produced synergistic effects. These double gene-edited CAR T cells proliferated faster and resisted exhaustion, ultimately curing mice of aggressive leukemia. The CELLFIE platform provides a versatile toolkit for accelerating the discovery of next-generation immune cell therapies, which could expand their use to solid tumors and other diseases.
Image credit: Nature (2025). DOI: 10.1038/s41586-025-09507-9 (Medical Express)
By CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Article can be accessed on: Medical Express
