面向早期 CAR 设计与候选发现的高通量单细胞跨谱系 CAR 文库筛选

Chimeric antigen receptor T cell therapy (CAR-T) has demonstrated promising efficacy in hematological malignancies, but translating that success to solid tumors remains challenging.

Here, we construct a CAR library comprising approximately 1000 variants targeting prostate-specific membrane antigen by recombining transmembrane (TM), co-stimulatory, and activation domains from Natural Killer (NK) and T cell receptors.

Single-cell screening identifies ICOS TM -containing variants with improved T cell activation; NK-derived activation domains, such as DAP10 , DAP12 , and FcR , further augment the effector capacity. Gene regulatory network analysis reveals that CAR variants with elevated expression of T cell-activation-related transcription factors correlates with enhanced cell function.

Overall, our study advances early-stage CAR design by expanding the repertoire of structural components from diverse immune cells, providing a scalable platform for identifying candidates with functional profiles comparable to clinical benchmarks.