{
  "abstract": "Background: Tumor epigenetic reprogramming serves as a critical hallmark of cancer, fostering transcriptional plasticity of gene expression and driving alterations in the suppressive inflammatory responses within the tumor microenvironment, which pose significant challenges to the advancement of novel CAR-macrophage (CAR-M)-based antitumor therapies. However, it remains limited mechanistic investigations exploring how epigenetic reprogramming strategies impact the efficacy of CAR-M treatments.\n\nMethods: Human epidermal growth factor receptor 2 (HER2)-targeted CAR-Ms containing either an α1β1 integrin-mediated Fc-gamma receptor I (FcγRI) or CD3ζ signaling domain were generated and compared for tumor-directed migration and antitumor activity. HER2-positive tumor cells were pretreated with decitabine (DAC). CAR-M function, tumor-cell death, transcriptomic and inflammatory pathway changes, tumor immune remodeling, and therapeutic efficacy were assessed using in vitro assays, RNA sequencing, and murine tumor and metastasis models. Full-dose and half-dose CAR-M regimens were evaluated.\n\nResults: α1β1 integrin-FcγRI CAR-Ms displayed significantly greater migration toward HER2-positive tumor cells than CD3ζ CAR-Ms. DAC potentiated anti-HER2 CAR-M activity by reprogramming tumor-cell gene expression and shifting the dominant cell-death mode from apoptosis to gasdermin E (GSDME)-dependent pyroptosis. RNA sequencing demonstrated enrichment of inflammatory immune-response programs, including nuclear factor kappa B and Janus kinase-signal transducer and activator of transcription signaling, after DAC treatment. DAC also favorably remodeled the tumor immune microenvironment, thereby supporting CAR-M activity. In murine models, DAC plus CAR-M therapy enhanced inflammatory antitumor immunity and improved control of primary tumor growth and metastatic disease compared with CAR-M monotherapy. Notably, DAC pretreatment combined with half-dose CAR-Ms achieved therapeutic efficacy comparable to that of full-dose CAR-M treatment.\n\nConclusions: DAC-mediated DNA demethylation sensitizes HER2-positive tumors to CAR-M therapy through GSDME-dependent pyroptosis, activation of inflammatory signaling, and favorable remodeling of the tumor microenvironment. Epigenetic priming may improve CAR-M efficacy while reducing the required cell dose, supporting further translational development of this combination strategy for solid tumors.",
  "abstract_shown": true,
  "affiliations": [
    "School of Life Science and Technology, Xidian University, Xi’an, China",
    "Engineering Research Center of Molecular & Neuroimaging, Xidian University, Xi’an, China",
    "Department of Gastrointestinal Surgery Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China",
    "The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China",
    "Shaanxi Provincial Hospital of Traditional Chinese Medicine, Xi’an, China",
    "Department of General Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 14,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Wenhui Chu"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Yuanhui Xu"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Liting Lin"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Zixuan Ye"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Meixi Jiang"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Yuanyuan Li"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Xiaoya Deng"
    },
    {
      "affs": [
        2
      ],
      "name": "Ziqi Qiuzhuo"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Yuqiong Xia"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Xianghan Zhang"
    },
    {
      "affs": [
        3
      ],
      "name": "Lili Jiang"
    },
    {
      "affs": [
        4
      ],
      "name": "Lin Gu"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Pengbo Ning",
      "orcid": "0000-0002-2571-2202"
    },
    {
      "affs": [
        2,
        5
      ],
      "name": "Zhihui Chen"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/719m9yp04fahr.bib",
  "cited_by": 0,
  "doi": "10.1136/jitc-2026-015535",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13723923/",
  "id": "719m9yp04fahr",
  "issns": [
    "2051-1426"
  ],
  "landing_url": "https://doi.org/10.1136/jitc-2026-015535",
  "language": "en",
  "licence": "CC-BY-NC-4.0",
  "licence_label": "CC BY-NC 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "1506"
    ],
    [
      "heading",
      "2436"
    ],
    [
      "heading",
      "Immune Cell Therapies and Immune Cell Engineering"
    ],
    [
      "heading",
      "Original Research"
    ],
    [
      "openalex",
      "2730|CAR-T cell therapy research"
    ]
  ],
  "openalex": "W7224783425",
  "pdf_url": null,
  "pmcid": "PMC13723923",
  "pmid": "42963101",
  "published": "2026-10-30",
  "publisher": "BMJ Publishing Group",
  "ris": "https://research.draconitic.com/paper/719m9yp04fahr.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T12:22:28Z",
      "native_id": "PMC13723923",
      "source": "pmc",
      "url": "https://doi.org/10.1136/jitc-2026-015535"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|CAR-T cell therapy research",
      "subfield": "oncology"
    }
  ],
  "title": "Epigenetic demethylation sensitizes cancer cells to CAR-M triggered pyroptosis and remodels inflammatory immune responses in the tumor microenvironment to potentiate CAR-M cell therapy",
  "title_text": "Epigenetic demethylation sensitizes cancer cells to CAR-M triggered pyroptosis and remodels inflammatory immune responses in the tumor microenvironment to potentiate CAR-M cell therapy",
  "type": "peer-reviewed",
  "updated_at": "2026-11-05T12:20:39Z",
  "url": "https://research.draconitic.com/paper/719m9yp04fahr",
  "venue": "Journal for Immunotherapy of Cancer",
  "versions": []
}