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However, its broader clinical application remains constrained by complex autologous manufacturing, high cost, limited scalability, variable product quality, suboptimal efficacy in solid tumors, and treatment\u2010related toxicities. To address these challenges, recent advances in CAR\u2010T cell therapy can be viewed across four interconnected dimensions: functional engineering, manufacturing innovation, alternative cell sources, and in\u00a0vivo CAR programming. Functional engineering includes cytokine\u2010armored, checkpoint\u2010resistant, multi\u2010targeting, and modular or switchable CAR platforms designed to enhance efficacy, persistence, and safety. In parallel, manufacturing innovations such as shortened culture protocols, automated closed systems, and preservation of less differentiated T\u2010cell states aim to improve product potency while reducing production time and complexity. Alternative cell sources, including allogeneic donor\u2010derived and induced pluripotent stem cell (iPSC)\u2010derived platforms, may further enable standardized, scalable, and potentially off\u2010the\u2010shelf therapies. Finally, in\u00a0vivo CAR programming has emerged as a fourth dimension in which endogenous immune cells are directly engineered within patients using viral or non\u2010viral gene delivery systems. This review summarizes these interconnected advances and discusses how they may collectively shape the next generation of CAR\u2010based immune therapies.<\/jats:p>","DOI":"10.1111\/cas.70567","type":"journal-article","created":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T03:30:51Z","timestamp":1792380651000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Evolution of\n                    <scp>CAR<\/scp>\n                    \u2010T Therapy: Functional Engineering, Manufacturing Innovation, and Future In\u00a0Vivo Strategies"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1519-893X","authenticated-orcid":false,"given":"Yukimi","family":"Sakoda","sequence":"first","affiliation":[{"name":"Department of Immunology Yamaguchi University Graduate School of Medicine  Ube Yamaguchi Japan"},{"name":"Research Institute for Cell Design Medical Science Yamaguchi University  Ube Yamaguchi 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