{
  "abstract": "Chimeric antigen receptor (CAR) T-cell therapy has achieved remarkable and durable responses in hematologic malignancies, but its efficacy in solid tumors remains limited and frequently transient. In this Review, we propose that interacting tumor barriers divert persistently engaged CAR-T cells toward dysfunctional and exhausted states. Defective trafficking, antigen heterogeneity, incomplete tumor clearance, metabolic deprivation, stromal exclusion, immunosuppressive cellular networks, inhibitory cytokines, chronic CAR signaling, and manufacturing-imprinted stress collectively shape the stimulation history and functional trajectory of CAR T-cells. Mechanistically, these pressures converge on NFAT–AP-1 imbalance, TOX/TOX2 and NR4A activation, mitochondrial dysfunction, and exhaustion-associated epigenetic remodeling. This process creates a clinically relevant continuum between TCF1-positive progenitor-exhausted cells that retain self-renewal and checkpoint-responsive proliferative potential, and terminally exhausted cells with limited regenerative capacity. Building on this failure–pressure–fate model, we propose a mechanism-informed therapy framework that relates dominant failure mechanisms and residual CAR T-cell plasticity to potential intervention priorities. This approach may help match combination strategies to the dominant tumor pressure and CAR T-cell state, including stromal remodeling, metabolic engineering, cytokine armoring, checkpoint modulation, epigenetic intervention, and remanufacturing. Overall, this Review provides a fate-based framework for designing next-generation CAR T-cell therapies capable of achieving durable control in solid tumors.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Pathology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China",
    "The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China",
    "Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan, 610072, China",
    "School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, China",
    "Personalized Drug Research and Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, Chengdu, Sichuan, 610072, China",
    "Chuan-Yu Joint Key Laboratory for Pathological and Laboratory Medicine, Jinfeng Laboratory, Chongqing, 400039, China"
  ],
  "article_type": "review article",
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "affs": [
        0,
        1,
        2,
        3
      ],
      "name": "Pei Wang"
    },
    {
      "affs": [
        1,
        2,
        3
      ],
      "name": "Yuehong Zhou"
    },
    {
      "affs": [
        3
      ],
      "name": "Yuan Wang"
    },
    {
      "affs": [
        1,
        2,
        3
      ],
      "name": "Yangyang Li"
    },
    {
      "affs": [
        0
      ],
      "name": "Xue Xiao"
    },
    {
      "affs": [
        1,
        2,
        3,
        4,
        5
      ],
      "name": "Chenhui Wang"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/e3hsahhx85ydn.bib",
  "cited_by": 0,
  "doi": "10.1016/j.cellin.2026.100377",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13696342/",
  "id": "e3hsahhx85ydn",
  "issns": [
    "2772-8927"
  ],
  "landing_url": "https://doi.org/10.1016/j.cellin.2026.100377",
  "language": "en",
  "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": [
    [
      "heading",
      "Review"
    ],
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      "openalex",
      "2730|CAR-T cell therapy research"
    ]
  ],
  "openalex": "W7215089436",
  "pdf_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13696342/pdf/?tool=EBI",
  "pmcid": "PMC13696342",
  "pmid": "42935544",
  "published": "2026-10-01",
  "publisher": "Elsevier",
  "ris": "https://research.draconitic.com/paper/e3hsahhx85ydn.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:43Z",
      "native_id": "PMC13696342",
      "source": "pmc",
      "url": "https://doi.org/10.1016/j.cellin.2026.100377"
    },
    {
      "first_seen": "2026-10-30T12:21:45Z",
      "native_id": "PMC:PMC13696342",
      "source": "europepmc",
      "url": "https://europepmc.org/article/PMC/PMC13696342"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|CAR-T cell therapy research",
      "subfield": "oncology"
    }
  ],
  "title": "From failure to fate: Pressure-driven exhaustion in solid-tumor CAR T-cell therapy",
  "title_text": "From failure to fate: Pressure-driven exhaustion in solid-tumor CAR T-cell therapy",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:33:42Z",
  "url": "https://research.draconitic.com/paper/e3hsahhx85ydn",
  "venue": "Cell Insight",
  "versions": []
}