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Immunol."],"abstract":"<jats:p>Chimeric antigen receptor (CAR)-T cell therapy for colorectal cancer (CRC) faces three major barriers: antigen heterogeneity, off\u2212tumor toxicity, and the efficacy\u2212safety trade\u2212off. To overcome these obstacles, next\u2212generation engineering strategies have emerged, including: (1) novel CRC\u2212associated targets with improved tissue restriction; (2) architectural innovations such as armored CARs, optimized signaling (1XX, 28\u2212\u0394IL2RB\u2212z(YXXQ)), and cytokine\u2212arming; (3) combinatorial antigen\u2212sensing circuits (AND\/OR\/NOT gates, SUPRA, synNotch); and (4) CRISPR\u2212based editing for exhaustion\u2212related knockouts (e.g., PD\u22121, Fas, TGFBR2) and site\u2212specific CAR knock\u2212in. Clinical evidence has demonstrated objective responses and disease stabilization in subsets of patients. However, the immunosuppressive tumor microenvironment\u2014including inhibitory cells, dense stroma, and metabolic dysfunction\u2014remains a critical hurdle limiting CAR\u2212T persistence. Future directions should prioritize molecular typing\u2212guided intervention, universal CAR\u2212T, multicellular platforms (CAR\u2212NK, CAR\u2212M), and interdisciplinary collaboration. This review provides a framework for designing next\u2212generation CAR\u2212T therapies capable of achieving durable remissions in advanced CRC.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1829723","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T05:27:09Z","timestamp":1782192429000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Next-generation CAR-T engineering for colorectal cancer: integrating targets, tumor microenvironment barriers, and emerging strategies"],"prefix":"10.3389","volume":"17","author":[{"given":"Yajuan","family":"Yang","sequence":"first","affiliation":[{"name":"Henan Province Hospital of Traditional Chinese Medicine, The Second Affiliated Hospital of Henan University of Chinese Medicine","place":["Zhengzhou, Henan, 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