In vivo CRISPR screens reveal GPCR–GNAS axis as a brake on T cell therapy in solid tumors

Nature reports a scalable in vivo platform for genome-wide CRISPR screens in human T cells within solid tumors. Two screens found that GPCR signaling via the P2RY8–Gα13 axis limits T cell tumor infiltration, while GNAS (Gαs) drives intratumoral T cell dysfunction. Knocking out GNAS enhances T cell fitness and antitumor efficacy across multiple CAR/TCR models, and combining P2RY8 and GNAS edits yields even better tumor control, enabling systematic genetic improvements for solid-tumor T cell therapies.