{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T05:53:42Z","timestamp":1791266022346,"version":"4.1.0"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable remission rates exceeding 80% in relapsed\/refractory pediatric B-cell acute lymphoblastic leukemia (B-ALL), yet 40\u201350% of patients eventually relapse within the first year. This therapeutic ceiling is not a single failure mode but the convergence of at least four interrelated layers: loss of CAR-T persistence, antigen escape driven by CD19 splicing variants and lineage switch, CAR-T cell-intrinsic exhaustion from chronic tonic signaling, and an immunosuppressive bone marrow microenvironment that actively extinguishes effector function. Our systematic analysis of 226 pediatric-eligible CAR-T trials shows that 95.6% are Phase I\u2013II, 3.5% (8\/226) are registered as Phase III\/IV, and 58 of 102 completed trials (56.9%) had no outcome recorded in the source database. In this Perspective, we synthesize the molecular mechanisms of CAR-T resistance, contextualize them within the current clinical trial landscape, and critically evaluate emerging engineering strategies\u2014from dual-targeting and armored CAR architectures to CRISPR-edited allogeneic products and\n                    <jats:italic>in vivo<\/jats:italic>\n                    mRNA delivery. We argue that progress depends on both smarter receptor design and structural reforms in trial design, outcome transparency and global collaboration.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1909384","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T05:21:15Z","timestamp":1791264075000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Resistance mechanisms and translational bottlenecks in CAR-T cell therapy for pediatric acute lymphoblastic leukemia: a perspective"],"prefix":"10.3389","volume":"17","author":[{"given":"JiLi","family":"Xu","sequence":"first","affiliation":[{"name":"College of Traditional Chinese Medicine, Shandong Medical and Pharmaceutical University","place":["Yantai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Sui","sequence":"additional","affiliation":[{"name":"Gaomi Maternity and Child Health Hospital","place":["Gaomi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenzhe","family":"Yang","sequence":"additional","affiliation":[{"name":"Shandong University of Traditional Chinese Medicine","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Xu","sequence":"additional","affiliation":[{"name":"Shandong Second Medical University","place":["Weifang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingliang","family":"Shan","sequence":"additional","affiliation":[{"name":"Gaomi Maternity and Child Health Hospital","place":["Gaomi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1709866","article-title":"Tisagenlecleucel in children and young adults with B-cell lymphoblastic 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