{
  "abstract": "Chimeric antigen receptor-macrophages (CAR-Ms) represent a promising platform for solid tumors, but barriers limiting durable responses remain incompletely defined. Antigen shedding may be a key barrier because, unlike T cells, macrophages require sustained antigen engagement for effective phagocytosis. However, whether shed antigen directly impairs CAR-M function has not been established. Using mesothelin (MSLN) as a model target, we generated CAR-Ms targeting either an N-terminal epitope (SS1) or a membrane-proximal, non-shed epitope (15B6). Shed MSLN markedly impaired the phagocytic and cytotoxic activity of SS1 CAR-Ms, establishing antigen shedding as a direct functional barrier. In contrast, 15B6 CAR-Ms remained largely resistant and showed stronger antigen-specific activity across multiple MSLN⁺ tumor cells, demonstrating that rational epitope selection can overcome this barrier. In immunocompetent, MSLN-tolerant transgenic mouse models of colorectal and pancreatic cancer, 15B6 CAR-Ms demonstrated superior anti-tumor activity. In colorectal tumor-bearing mice, a single infusion of 15B6 CAR-Ms significantly prolonged survival, with 35% achieving complete tumor regression. Rechallenge of cured mice with MSLN⁻ tumor cells resulted in complete tumor rejection, suggesting the development of durable systemic anti-tumor immunity. Together, these findings identify antigen shedding as a critical barrier and support epitope selection as an important design strategy for CAR-M therapies targeting shed tumor antigens.",
  "abstract_shown": true,
  "affiliations": [
    "Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.",
    "Evotec International GmbH, Marie-Curie-Str. 7, 37079 Goettingen, Germany."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Wenlong Liu"
    },
    {
      "affs": [
        0
      ],
      "name": "Xiufen Liu"
    },
    {
      "affs": [
        0
      ],
      "name": "Seraphim Kozlov"
    },
    {
      "affs": [
        0
      ],
      "name": "Qi Zhou"
    },
    {
      "affs": [
        0
      ],
      "name": "Masanori Onda"
    },
    {
      "affs": [
        1
      ],
      "name": "Nadja Wagner"
    },
    {
      "affs": [
        0
      ],
      "name": "Ira Pastan"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/ctq5vt649seyn.bib",
  "cited_by": 0,
  "doi": "10.1016/j.omton.2026.201354",
  "fulltext_url": "https://europepmc.org/articles/PMC13692139",
  "id": "ctq5vt649seyn",
  "issns": [
    "2950-3299"
  ],
  "landing_url": "https://europepmc.org/article/MED/42920992",
  "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": "W7214938222",
  "pdf_url": "https://europepmc.org/articles/PMC13692139?pdf=render",
  "pmcid": "PMC13692139",
  "pmid": "42920992",
  "published": "2026-09-30",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/ctq5vt649seyn.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:36Z",
      "native_id": "MED:42920992",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42920992"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|CAR-T cell therapy research",
      "subfield": "oncology"
    }
  ],
  "title": "Epitope selection overcomes antigen shedding to enable effective CAR-M therapy in solid tumors.",
  "title_text": "Epitope selection overcomes antigen shedding to enable effective CAR-M therapy in solid tumors.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:20:36Z",
  "url": "https://research.draconitic.com/paper/ctq5vt649seyn",
  "venue": "Molecular therapy. Oncology",
  "versions": []
}