CAR-T Entering a New "Phase": Improving CAR-T Function by Harnessing Phase Separation

Biomolecular condensation has emerged as a general principle in organizing biological processes, including immune response. Xu and colleagues recently reported that the cytoplasmic tail of the CD3 epsilon subunit of the T-cell receptor complex, when fused to a chimeric antigen receptor (CAR), can promote CAR condensation by liquid-liquid phase separation. Through sequence engineering, the authors identified modified CD3 epsilon sequences that enhance the maturation of the immunologic synapse and coreceptor signaling, leading to an improvement in cytotoxicity in vitro and antitumor effects in mouse xenograft models. These results demonstrated that biomolecular condensation could be exploited to improve the function of CAR-T cells, highlighting an exciting strategy for developing next-generation cell therapies.