{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T04:52:15Z","timestamp":1794027135888,"version":"4.8.0"},"reference-count":260,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated remarkable clinical efficacy across a spectrum of hematological malignancies, with particularly profound responses observed in B-cell leukemias, lymphomas, and multiple myeloma. However, the clinical benefits of CAR-T cell therapy have not yet been effectively extended to most solid tumors. This limitation arises from multiple biological and structural barriers, including the paucity of truly tumor-specific antigens, variable antigen expression and loss, inefficient trafficking and infiltration, and the presence of a highly immunosuppressive tumor microenvironment (TME). These obstacles not only restrict tumor recognition and intratumoral accumulation but also impair CAR-T-cell persistence, cytotoxicity, and durable tumor control, while promoting immune escape and increasing the likelihood of on-target, off-tumor toxicity. To address these challenges, diverse engineering strategies are being developed to improve the safety, efficacy, and adaptability of CAR-T cell therapy in solid tumors. These include Boolean logic-gated receptors, multi-antigen and retargeting platforms, locoregional delivery and trafficking-enhancing approaches, checkpoint blockade, armored CAR-T cells, synthetic receptors that rewire inhibitory signals, and emerging\n                    <jats:italic>in vivo<\/jats:italic>\n                    engineering approaches. In this review, we discuss how these next-generation engineering strategies are being designed to overcome the obstacles that constrain CAR-T-cell efficacy in solid tumors and to guide the development of safer and more effective therapeutic platforms.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1891408","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T11:27:57Z","timestamp":1785324477000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Engineering CAR-T cells for solid tumors: overcoming antigenic, trafficking, and microenvironmental barriers"],"prefix":"10.3389","volume":"17","author":[{"given":"Ziyan","family":"Kong","sequence":"first","affiliation":[{"name":"School of Biological Science and Medical Engineering, Southeast University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinke","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Biological Science and Medical Engineering, Southeast University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aar6711","article-title":"Car T cell immunotherapy for human cancer","volume":"359","author":"June","year":"2018","journal-title":"Science"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1080\/21645515.2024.2378543","article-title":"Approved Car-T therapies have reproducible efficacy and safety in clinical practice","volume":"20","author":"Goyco Vera","year":"2024","journal-title":"Hum Vaccin Immunother"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2025.102353","article-title":"Car-T cells in solid tumors: Challenges and 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