嵌合抗原受体（CAR）技术已经被临床应用于治疗血液恶性肿瘤；然而，实体肿瘤仍然对CAR治疗具有抵抗力。自然杀伤（NK）细胞可能是CAR导向方法的最优免疫细胞类别，因为它们天然具备抗肿瘤功能。在本研究中，我们试图通过向CAR添加一个细胞内支架蛋白结合位点来调整CAR免疫突触。我们采用了PDZ结合基序（PDZbm），它能够产生额外的支架交联，增强突触形成和NK CAR细胞极化。这种CAR设计的综合效果在体内外导致了效应细胞功能的增强。此外，我们使用T细胞并观察到类似的全局效应增强。突触调谐的CAR免疫细胞表现出增强的突触强度、分泌的细胞因子数量和丰度、对肿瘤细胞的增强杀伤能力以及在多种不同肿瘤模型中的延长生存时间，包括实体肿瘤。© 2023年。作者授权Springer Nature America，Inc.独家使用。

Chimeric antigen receptor (CAR) technologies have been clinically implemented for the treatment of hematological malignancies; however, solid tumors remain resilient to CAR therapeutics. Natural killer (NK) cells may provide an optimal class of immune cells for CAR-based approaches due to their inherent anti-tumor functionality. In this study, we sought to tune CAR immune synapses by adding an intracellular scaffolding protein binding site to the CAR. We employ a PDZ binding motif (PDZbm) that enables additional scaffolding crosslinks that enhance synapse formation and NK CAR cell polarization. Combined effects of this CAR design result in increased effector cell functionality in vitro and in vivo. Additionally, we used T cells and observed similar global enhancements in effector function. Synapse-tuned CAR immune cells exhibit amplified synaptic strength, number and abundance of secreted cytokines, enhanced killing of tumor cells and prolonged survival in numerous different tumor models, including solid tumors.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.