Gladstone/UCSF Team Publishes First In Vivo Genome-Wide CRISPR Screen in Human T Cells, Identifies Gene Edits That Supercharge CAR-T Against Solid Tumors

Researchers at the Gladstone-UCSF Institute of Genomic Immunology (Julia Carnevale, Alex Marson, Qi Liu) published in Nature the first genome-wide CRISPR screen performed directly inside living tumors rather than in cell culture, testing nearly 20,000 genes in human T cells engineered into mice bearing solid tumors. The screen identified two gene edits that dramatically improved CAR-T efficacy against notoriously CAR-T-resistant solid tumors: deleting P2RY8 removed a molecular brake that normally restricts T cell infiltration into tumors, while deleting GNAS boosted interferon-gamma production and blunted T cells' responsiveness to immunosuppressive signals in the tumor microenvironment. Combining both edits produced dramatic results in a lung cancer mouse model — two-thirds of treated mice remained tumor-free at study's end, versus zero in the unedited CAR-T control group. The in vivo screening platform itself is a methodological breakthrough: it can reveal therapeutic targets that conventional cell-culture screens would miss because they don't capture the immunosuppressive tumor microenvironment.