美国加州大学圣地亚哥分校王英晓团队提出了工程声源回声-CAR T细胞。相关论文于2025年4月2日发表在《细胞》杂志上。
小组设计声源EchoBack-CAR T细胞，将从文库中筛选的超敏感热休克启动子与CAR信号传导的正反馈回路相结合，使CAR在聚焦超声（FUS）刺激下持久表达。在3D胶质母细胞瘤（GBM）模型中，靶向双胞苷GD2的EchoBack-hGD2CAR T细胞表现出强大的细胞毒性和持久性。在小鼠实验中，EchoBack-hGD2CAR - T细胞抑制GBM而无肿瘤外毒性，并且优于其组成对应物。单细胞RNA测序显示，与标准CAR - T细胞相比，EchoBack-CAR - T细胞的细胞毒性增强，衰竭减少。该EchoBack设计进一步适用于前列腺特异性膜抗原（EchoBack- psmacar）用于前列腺癌治疗，显示出持久的肿瘤抑制和最小的肿瘤外毒性。因此，声源EchoBack-CAR - T细胞可以作为一种多功能、高效和安全的实体瘤治疗策略。
据介绍，嵌合抗原受体（CAR） T细胞治疗实体肿瘤面临着靶外毒性、衰竭和有限的T细胞持久性等挑战。
附：英文原文
Title: Engineering sonogenetic EchoBack-CAR T cells
Author: Longwei Liu, Peixiang He, Yuxuan Wang, Fengyi Ma, Dulei Li, Zhiliang Bai, Yunjia Qu, Linshan Zhu, Chi Woo Yoon, Xi Yu, Yixuan Huang, Zhengyu Liang, Yiming Zhang, Kunshu Liu, Tianze Guo, Yushun Zeng, Qifa Zhou, H. Kay Chung, Rong Fan, Yingxiao Wang
Issue&Volume: 2025-04-02
Abstract: Chimeric antigen receptor (CAR) T cell therapy for solid tumors encounters challenges such as on-target off-tumor toxicity, exhaustion, and limited T cell persistence. Here, we engineer sonogenetic EchoBack-CAR T cells using an ultrasensitive heat-shock promoter screened from a library and integrated with a positive feedback loop from CAR signaling, enabling long-lasting CAR expression upon focused-ultrasound (FUS) stimulation. EchoBack-hGD2CAR T cells, targeting disialoganglioside GD2, exhibited potent cytotoxicity and persistence in 3D glioblastoma (GBM) models. In mice, EchoBack-hGD2CAR T cells suppressed GBM without off-tumor toxicity and outperformed their constitutive counterparts. Single-cell RNA sequencing revealed enhanced cytotoxicity and reduced exhaustion in EchoBack-CAR T cells compared with the standard CAR T cells. This EchoBack design was further adapted to target prostate-specific membrane antigen (EchoBack-PSMACAR) for prostate cancer treatment, demonstrating long-lasting tumor suppression with minimal off-tumor toxicity. Thus, the sonogenetic EchoBack-CAR T cells can serve as a versatile, efficient, and safe strategy for solid tumor treatment.
DOI: 10.1016/j.cell.2025.02.035
Source: https://www.cell.com/cell/abstract/S0092-8674(25)00271-5