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To address this, we engineered a translational control system for CAR expression based on Genetic Code Expansion (GCE), enabling tight, dose\u2010dependent, and function\u2010preserving regulation through nonsense codon suppression via noncanonical amino acids (ncAAs). By introducing amber stop codons into CAR constructs and engineered aminoacyl\u2010tRNA synthetase and tRNA pair, we developed a leak\u2010free regulatory module applicable in both Jurkat and primary human T cells. NcAA\u2010treated GCE\u2010CAR\u2010T cells exhibited antigen\u2010specific cytotoxicity and cytokine secretion comparable to wild\u2010type CAR\u2010T cells. In a xenograft mouse model, tumor\u2010specific immune responses were observed only upon ncAA administration, with untreated controls showing no therapeutic effect. This work establishes a stringent, fast\u2010acting translational switch that enables precise modulation of CAR\u2010T cell function without compromising efficacy, offering a promising platform for next\u2010generation programmable cell therapies.<\/jats:p>","DOI":"10.1002\/advs.75501","type":"journal-article","created":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T11:18:56Z","timestamp":1777893536000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic Code Expanded T Cell for Controllable Immunotherapy"],"prefix":"10.1002","volume":"13","author":[{"given":"Xue","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Natural and Biomimetic Drugs, Chemical Biology Center, Institute of Advanced Clinical Medicine, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences Peking University  Beijing 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