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Adv."],"published-print":{"date-parts":[[2026,6,12]]},"abstract":"<jats:p>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\u2013specific promoters such as enAFP in hepatocellular carcinoma to enable both spatial and cell type\u2013specific targeting. Together, SHIFTERS provides a modular, tumor-constrained, ultrasound-controllable platform to improve the precision and efficacy of CAR-T therapy for solid tumors.<\/jats:p>","DOI":"10.1126\/sciadv.aed0666","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T17:58:42Z","timestamp":1781114322000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Ultrasound priming gated by solid tumor hallmarks to guide CAR-T therapy"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6280-5902","authenticated-orcid":true,"given":"Tianze","family":"Guo","sequence":"first","affiliation":[{"name":"Alfred E. 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