{
  "abstract": "Colorectal cancer is a common digestive malignancy. Neoadjuvant chemotherapy (NAC) can downstage tumors and increase R0 resection rates. In colorectal cancer specimens with favorable pathological regression after NAC, we observed CD68⁺ multinucleated giant cells (MGCs) preferentially localized in apoptotic cell-rich areas, whereas they were rarely detected in non-NAC specimens. However, the mechanisms driving MGC formation and their functional significance remain unclear. We established an in vitro apoptotic cell-macrophage co-culture system to assess how apoptotic cell burden and efferocytosis regulate macrophage fusion. The TREM2/TYROBP signaling axis was examined using molecular and pharmacological approaches. RNA sequencing, pathway enrichment, lysosome- and metabolism-related transcriptional analyses, and secretory profiling were performed to characterize efferocytosis-induced MGCs. Their effects on colorectal cancer cells and the tumor microenvironment were further evaluated in vitro and in tumor-bearing mouse models. Excessive apoptotic cell burden markedly promoted macrophage fusion and upregulated the fusion-related molecules DCSTAMP/Dcstamp and CDH1/Cdh1. Apoptotic cell overload shifted macrophages from a homeostatic/efferocytic state toward a fusion-prone MGC phenotype. TYROBP/Tyrobp knockdown or loss inhibited macrophage fusion. Mechanistically, apoptotic cell overload activated the TREM2/TYROBP-MAPK/c-FOS-DCSTAMP axis, thereby enhancing DCSTAMP transcription and macrophage fusion. Efferocytosis-induced MGCs showed reduced lysosome-related transcriptional programs and an altered secretory profile, including increased TNF-α expression. Functionally, MGCs inhibited colorectal cancer cell growth in vitro. In tumor-bearing mice, MGCs reduced CD206⁺ macrophage and regulatory T-cell abundance while increasing CD8⁺ T-cell infiltration, thereby contributing to tumor growth suppression. Together, these findings identify efferocytosis-induced MGCs as a distinct macrophage state with altered lysosomal and secretory programs, anti-tumor activity, and the potential to remodel the tumor microenvironment.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China.",
    "Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.",
    "Department of Human Anatomy, School of Basic Medical Sciences, Anhui Medical University, Hefei, China.",
    "Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China. yfy1052759@fy.ahmu.edu.cn.",
    "Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China. luming@ahmu.edu.cn."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Jiaxin Xue"
    },
    {
      "affs": [
        0
      ],
      "name": "Zhiwei Wang"
    },
    {
      "affs": [
        1
      ],
      "name": "Xiaoliang Zhang"
    },
    {
      "affs": [
        0
      ],
      "name": "Sen Xu"
    },
    {
      "affs": [
        0
      ],
      "name": "Shuang Wu"
    },
    {
      "affs": [
        0
      ],
      "name": "Xiaoyue Sun"
    },
    {
      "affs": [
        2
      ],
      "name": "Meiqi Li"
    },
    {
      "affs": [
        2
      ],
      "name": "Xueyan Wu"
    },
    {
      "affs": [
        3
      ],
      "name": "Zhangming Chen"
    },
    {
      "affs": [
        4
      ],
      "name": "Ming Lu",
      "orcid": "0000-0003-3044-8423"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/9mkbxjdyx0m74.bib",
  "cited_by": 1,
  "doi": "10.1038/s41419-026-09320-w",
  "fulltext_url": "https://europepmc.org/articles/PMC13694713",
  "id": "9mkbxjdyx0m74",
  "issns": [
    "2041-4889"
  ],
  "landing_url": "https://europepmc.org/article/MED/42919826",
  "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": [
    [
      "lcc",
      "QH573-671"
    ],
    [
      "openalex",
      "2403|Phagocytosis and Immune Regulation"
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  "openalex": "W7220459338",
  "pdf_url": "https://europepmc.org/articles/PMC13694713?pdf=render",
  "pmcid": "PMC13694713",
  "pmid": "42919826",
  "published": "2026-10-05",
  "publisher": "Nature Publishing Group",
  "ris": "https://research.draconitic.com/paper/9mkbxjdyx0m74.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:36Z",
      "native_id": "MED:42919826",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42919826"
    },
    {
      "first_seen": "2026-10-30T13:46:30Z",
      "native_id": "215fa2882c7d43149701fef7dee13dda",
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      "url": "https://doi.org/10.1038/s41419-026-09320-w"
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  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2403|Phagocytosis and Immune Regulation",
      "subfield": "immunology"
    }
  ],
  "title": "Apoptotic cell overload drives multinucleated giant cell formation after neoadjuvant chemotherapy in colorectal cancer: molecular mechanisms and tumor-suppressive effects.",
  "title_text": "Apoptotic cell overload drives multinucleated giant cell formation after neoadjuvant chemotherapy in colorectal cancer: molecular mechanisms and tumor-suppressive effects.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T13:46:30Z",
  "url": "https://research.draconitic.com/paper/9mkbxjdyx0m74",
  "venue": "Cell death & disease",
  "versions": []
}