Ultrasound priming gated by solid tumor hallmarks to guide CAR-T therapy
- Tianze Guo
- Ziyue Zhu
- Yunjia Qu
- Xi Yu
- Linshan Zhu
- Yuxuan Wang
- Kunshu Liu
- Jiaxin Cui
- Xue Dong
- Chi-Woo Yoon
- Cem Yigit Kilic
- Peixiang He
- Shuangquan Gou
- Yushun Zeng
- Priyankan Datta
- Qifa Zhou
- Hongquan Xu
- Ishwar K. Puri
- Longwei Liu
- Keyue Shen
- Yingxiao Wang
2026-06-10
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.