{
  "abstract": "Chimeric antigen receptor (CAR)-T cell therapy has achieved limited success against solid tumors, in part because excessive tonic signaling drives premature T cell exhaustion, as exemplified by CSPG4 and GD2 CARs. Here, we demonstrate that replacing the dimeric CD28 transmembrane (TM) domain with the monomeric PD-L1 TM domain substantially mitigates tonic signaling. The PD-L1 TM displays a smaller tilt angle and lower hydrophobic thickness, enabling a better membrane fit that minimizes spontaneous CAR clustering. This structural feature reduces tonic signaling and exhaustion and confers superior proliferation and memory preservation, resulting in enhanced and sustained tumor killing in vitro and in vivo. Mechanistically, these benefits were associated with attenuated phosphorylation across the CD3ζ-ZAP70-PLC-γ1/MAPK/AKT/NF-κB axis, downregulation of exhaustion-associated genes, and upregulation of stemness- and memory-related programs. Collectively, our findings establish that the PD-L1 TM swap is a modular and broadly applicable strategy to suppress CAR tonic signaling and promote durable, memory-biased CAR-T responses against solid tumors.",
  "abstract_shown": true,
  "affiliations": [
    "ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai 200031, China.",
    "Shanghai Key Laboratory of Gene Editing and Cell Therapy for Rare Diseases, Fudan University, Shanghai 200031, China.",
    "School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.",
    "Institute of Biomedicine Sciences & Shanghai Stomatological Hospital, Fudan University, Shanghai, China.",
    "Changping Laboratory, Beijing 102206, China."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 14,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Liang Zhang"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Xiang Xu"
    },
    {
      "affs": [
        0
      ],
      "name": "Haiwen Yu"
    },
    {
      "affs": [
        2
      ],
      "name": "Shizhen Qiu"
    },
    {
      "affs": [
        0
      ],
      "name": "Zhitong Wang"
    },
    {
      "affs": [
        0
      ],
      "name": "Yinying Chu"
    },
    {
      "affs": [
        0
      ],
      "name": "Guangfei Li"
    },
    {
      "affs": [
        0
      ],
      "name": "Yi Fang"
    },
    {
      "affs": [
        0
      ],
      "name": "Peijie He"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Haitao Wu"
    },
    {
      "affs": [
        0
      ],
      "name": "Lei Cheng"
    },
    {
      "affs": [
        3
      ],
      "name": "Hongxiu Yu"
    },
    {
      "affs": [
        2,
        4
      ],
      "name": "Haopeng Wang"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Jian Chen"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/e8t9949a2mn82.bib",
  "cited_by": 0,
  "doi": "10.1016/j.omton.2026.201364",
  "fulltext_url": "https://europepmc.org/articles/PMC13742466",
  "id": "e8t9949a2mn82",
  "issns": [
    "2950-3299"
  ],
  "landing_url": "https://europepmc.org/article/MED/42997611",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "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": "W7221828361",
  "pdf_url": "https://europepmc.org/articles/PMC13742466?pdf=render",
  "pmcid": "PMC13742466",
  "pmid": "42997611",
  "published": "2026-10-14",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/e8t9949a2mn82.ris",
  "sources": [
    {
      "first_seen": "2026-11-09T15:20:41Z",
      "native_id": "MED:42997611",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42997611"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|CAR-T cell therapy research",
      "subfield": "oncology"
    }
  ],
  "title": "PD-L1 transmembrane domain substitution overcomes CAR-T exhaustion driven by tonic signaling.",
  "title_text": "PD-L1 transmembrane domain substitution overcomes CAR-T exhaustion driven by tonic signaling.",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T15:20:41Z",
  "url": "https://research.draconitic.com/paper/e8t9949a2mn82",
  "venue": "Molecular therapy. Oncology",
  "versions": []
}