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 CD3ɛ subunit of TCR complex, when fused to CAR, can promote CAR condensation by liquid-liquid phase separation. Through sequence engineering, the authors identified modified CD3ɛ sequences that enhance the maturation of the immunological synapse and co-receptor signaling, leading to an improvement of cytotoxicity in vitro and anti-tumor 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.