{
  "abstract": "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 40–50% 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–II, 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—from dual-targeting and armored CAR architectures to CRISPR-edited allogeneic products and in vivo mRNA delivery. We argue that progress depends on both smarter receptor design and structural reforms in trial design, outcome transparency and global collaboration.",
  "abstract_shown": true,
  "affiliations": [
    "College of Traditional Chinese Medicine, Shandong Medical and Pharmaceutical University",
    "Gaomi Maternity and Child Health Hospital",
    "Shandong University of Traditional Chinese Medicine",
    "Shandong Second Medical University"
  ],
  "article_type": "research support, non u.s. gov't",
  "arxiv": null,
  "author_total": 5,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "JiLi Xu"
    },
    {
      "affs": [
        1
      ],
      "name": "Lili Sui"
    },
    {
      "affs": [
        2
      ],
      "name": "Wenzhe Yang"
    },
    {
      "affs": [
        3
      ],
      "name": "Li Xu"
    },
    {
      "affs": [
        1
      ],
      "name": "Mingliang Shan"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/659xxaad1zef7.bib",
  "cited_by": 0,
  "doi": "10.3389/fimmu.2026.1909384",
  "fulltext_url": "https://europepmc.org/articles/PMC13680422",
  "id": "659xxaad1zef7",
  "issns": [
    "1664-3224"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1909384/full",
  "language": "eng",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2730|CAR-T cell therapy research"
    ]
  ],
  "openalex": "W7220728632",
  "pdf_url": "https://europepmc.org/articles/PMC13680422?pdf=render",
  "pmcid": "PMC13680422",
  "pmid": "42903281",
  "published": "2026-10-06",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/659xxaad1zef7.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:15Z",
      "native_id": "10.3389/fimmu.2026.1909384",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1909384/full"
    },
    {
      "first_seen": "2026-10-30T12:19:57Z",
      "native_id": "MED:42903281",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42903281"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|CAR-T cell therapy research",
      "subfield": "oncology"
    }
  ],
  "title": "Resistance mechanisms and translational bottlenecks in CAR-T cell therapy for pediatric acute lymphoblastic leukemia: a perspective",
  "title_text": "Resistance mechanisms and translational bottlenecks in CAR-T cell therapy for pediatric acute lymphoblastic leukemia: a perspective",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:57Z",
  "url": "https://research.draconitic.com/paper/659xxaad1zef7",
  "venue": "Frontiers in Immunology",
  "versions": []
}