肿瘤细胞治疗研究
英文原题：Engineering sonogenetic EchoBack-CAR T cells.
用于实体瘤的嵌合抗原受体（CAR）T 细胞疗法面临脱靶毒性、耗竭以及 T 细胞持久性有限等挑战。
CAR-T 细胞治疗实体瘤面临靶向肿瘤同时作用于肿瘤外组织的毒性、细胞耗竭及持久性不足等挑战。本研究利用筛选自文库的超敏热休克启动子，并结合 CAR 信号正反馈环路，工程化构建声遗传 EchoBack-CAR T 细胞，使其在聚焦超声（FUS）刺激后实现持久 CAR 表达。靶向双唾液酸神经节苷脂 GD2 的 EchoBack-hGD2CAR T 细胞在 3D 胶质母细胞瘤（GBM）模型中表现出强效细胞毒性和持久性。在小鼠中，EchoBack-hGD2CAR T 细胞可抑制 GBM，未见肿瘤外组织毒性，且疗效优于组成型表达 CAR 的对照细胞。单细胞 RNA 测序显示，与标准 CAR-T 细胞相比，EchoBack-CAR T 细胞细胞毒性增强、耗竭减少。研究者进一步将 EchoBack 设计调整为靶向前列腺特异性膜抗原（EchoBack-PSMACAR），用于前列腺癌治疗；该设计实现了持久肿瘤抑制，且肿瘤外组织毒性极小。因此，声遗传 EchoBack-CAR T 细胞可作为治疗实体瘤的一种多用途、高效且安全的策略。
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.
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