Engineered T cells that express chimeric antigen receptors (CARs) have transformed the treatment of haematological cancers. CARs combine the tumour-antigen-binding function of antibodies with the signalling functions of the T-= cell receptor (TCR) ζ chain and co-stimulatory receptors. The resulting constructs aim to mimic the TCR-based and co-receptor-based activation of T cells. Although these have been successful for some types of cancer, new CAR formats are needed, to limit side effects and broaden their use to solid cancers. Insights into the mechanisms of TCR signalling, including the identification of signalling motifs that are not present in the TCR ζ chain and mechanistic insights in TCR activation, have enabled the development of CAR formats that outcompete the current CARs in preclinical mouse models and clinical trials. In this Perspective, we explore the mechanistic rationale behind new CAR designs.

表达嵌合抗原受体 （CAR） 的工程化 T 细胞改变了血液系统癌症的治疗。CAR 将抗体的肿瘤抗原结合功能与 T-= 细胞受体 （TCR） ζ链和共刺激受体的信号传导功能相结合。所得构建体旨在模拟基于 TCR 和基于共受体的 T 细胞激活。尽管这些方法对某些类型的癌症取得了成功，但需要新的 CAR 形式，以限制副作用并扩大其应用于实体癌。对 TCR 信号转导机制的见解，包括识别 TCR ζ链中不存在的信号转导基序以及 TCR 激活的机制见解，使 CAR 格式的开发成为可能，在临床前小鼠模型和临床试验中胜过当前的 CAR。在本期展望中，我们探讨了新 CAR 设计背后的机制原理。