肿瘤细胞治疗研究
英文原题：Ultrasound priming gated by solid tumor hallmarks to guide CAR-T therapy.
CAR-T 疗法在血液系统恶性肿瘤中高度有效，但在实体瘤中仍面临挑战。
CAR-T疗法治疗血液系统恶性肿瘤效果显著，但用于实体瘤仍面临挑战。为应对这一问题，我们开发了SHIFTERS（实体瘤标志诱导、聚焦超声触发的增强重编程系统），这是一种“与”门电路，可在聚焦超声（FUS）控制下，将肿瘤特征转换为临床验证过的抗原CD19。SHIFTERS采用分体式Gal4-VP64转录因子，其中一个模块由缺氧响应启动子驱动，另一个由FUS诱导的热休克启动子驱动，从而将CD19诱导限制在接受超声处理且具有相应肿瘤标志的区域。该设计可实现局部、稳健且持续的CD19表达，以激活并训练CD19 synNotch CAR-T细胞。在3D球体和体内模型中，缺氧门控SHIFTERS联合synNotch CAR-T细胞实现了强效肿瘤抑制，支持采用FUS进行引导式局部激活。SHIFTERS具有模块化特性，可适配肝细胞癌中的enAFP等肿瘤类型特异性启动子，从而实现空间和细胞类型双重特异性靶向。综上，SHIFTERS提供了一个模块化、受肿瘤限制且可由超声控制的平台，有望提高CAR-T治疗实体瘤的精准性和疗效。
CAR-T therapy is highly effective in hematologic malignancies but remains challenging in solid tumors. To address this challenge, here, we developed SHIFTERS (solid-tumor hallmark inducible, focused-ultrasound triggered enhanced reprogramming system), an AND-gated circuit that rewires tumor hallmarks into the clinically validated antigen CD19 under focused-ultrasound (FUS) control. SHIFTERS uses a split Gal4-VP64 transcription factor with one module driven by a hypoxia-responsive promoter and the other by a FUS-inducible heat-shock promoter, restricting CD19 induction to sonicated, hallmark-positive regions. This design enables robust, sustained local CD19 expression to activate and train CD19 synNotch CAR-T cells. In 3D spheroids and in vivo models, hypoxia-gated SHIFTERS combined with synNotch CAR-T cells achieved strong tumor suppression, supporting FUS-guided, localized activation. SHIFTERS is modular and can be adapted to tumor-type-specific promoters such as enAFP in hepatocellular carcinoma to enable both spatial and cell type-specific targeting. Together, SHIFTERS provides a modular, tumor-constrained, ultrasound-controllable platform to improve the precision and efficacy of CAR-T therapy for solid tumors.
MEMBER ACCOUNT
登录成功会直接打开下一页。
