{
  "abstract": "Colorectal liver metastases (CRLM) are a major cause of mortality in colorectal cancer and are characterised by a profoundly immunosuppressive tumour microenvironment in which tumour-associated macrophages (TAMs) play a central role. However, the molecular mechanisms driving TAM plasticity and maintenance remain poorly understood. Here, we investigated macrophage heterogeneity in CRLM and examined the contribution of the epigenetic regulator lysine-specific demethylase 1 (LSD1) to TAM polarisation. Analysis of patient-derived specimens by flow cytometry, immunohistochemistry and transcriptional profiling identified a population of large TAMs (L-TAMs) enriched in the peritumoral niche that displayed an immunosuppressive, M2-like phenotype and was associated with poor clinical outcome. In contrast, smaller TAMs (S-TAMs) exhibited a more inflammatory transcriptional programme, including increased IL1β expression. Tumour-conditioned media reproduced these distinct macrophage phenotypes in vitro, indicating that tumour-derived factors actively shape TAM identity. Pharmacological inhibition of LSD1 using baicalin or INCB059872 reduced the expression of CD206 and the immune checkpoint molecule PD-L1, consistent with macrophage reprogramming away from a tumour-promoting state. Collectively, these findings identify LSD1 as an epigenetic regulator of macrophage plasticity in CRLM, implicated in the maintenance of immunosuppressive TAM phenotypes, and potentially able to induce phenotypic reversion. Our findings identify LSD1 as a regulator of TAM phenotype and support further investigation of LSD1 targeting as a strategy to remodel the metastatic tumour microenvironment and potentially enhance anti-tumour immunity.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Health Sciences, Università del Piemonte Orientale, Novara, Italy.",
    "Laboratory of Hepatobiliary Immunopathology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.",
    "Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.",
    "Division of Hepatobiliary and General Surgery, Department of Surgery, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.",
    "Flow Cytometry Core, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.",
    "Spectral Flow Unit, Fondazione Istituto Nazionale Di Genetica Molecolare-INGM, Milan, Italy.",
    "Department of Pathology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.",
    "Unit of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.",
    "Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.",
    "Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.",
    "Department of Health Sciences, Università del Piemonte Orientale, Novara, Italy. matteo.donadon@uniupo.it.",
    "Division of General Surgery, University Maggiore Hospital Della Carità, Novara, Italy. matteo.donadon@uniupo.it."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 15,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Candela Cives-Losada"
    },
    {
      "affs": [
        1
      ],
      "name": "Cristiana Soldani"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Michela Anna Polidoro"
    },
    {
      "affs": [
        1
      ],
      "name": "Barbara Franceschini"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Flavio Milana"
    },
    {
      "affs": [
        1
      ],
      "name": "Aurora Gazzillo"
    },
    {
      "affs": [
        1
      ],
      "name": "Antonella Cammarota"
    },
    {
      "affs": [
        4
      ],
      "name": "Chiara Camisaschi"
    },
    {
      "affs": [
        5
      ],
      "name": "Francesca Clemente"
    },
    {
      "affs": [
        5
      ],
      "name": "Achille Anselmo"
    },
    {
      "affs": [
        2,
        6
      ],
      "name": "Luca Di Tommaso"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Guido Torzilli"
    },
    {
      "affs": [
        7,
        8
      ],
      "name": "Domenico Mavilio"
    },
    {
      "affs": [
        2,
        9
      ],
      "name": "Ana Lleo"
    },
    {
      "affs": [
        10,
        11
      ],
      "name": "Matteo Donadon",
      "orcid": "0000-0003-0296-7648"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/00sd5dm61gwn2.bib",
  "cited_by": 0,
  "doi": "10.1186/s43556-026-00602-5",
  "fulltext_url": "https://europepmc.org/articles/PMC13683283",
  "id": "00sd5dm61gwn2",
  "issns": [
    "2662-8651"
  ],
  "landing_url": "https://europepmc.org/article/MED/42900293",
  "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",
      "R"
    ],
    [
      "openalex",
      "2403|Immune cells in cancer"
    ]
  ],
  "openalex": "W7223025980",
  "pdf_url": "https://europepmc.org/articles/PMC13683283?pdf=render",
  "pmcid": "PMC13683283",
  "pmid": "42900293",
  "published": "2026-10-20",
  "publisher": "Springer",
  "ris": "https://research.draconitic.com/paper/00sd5dm61gwn2.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:32Z",
      "native_id": "MED:42900293",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42900293"
    },
    {
      "first_seen": "2026-10-30T13:45:35Z",
      "native_id": "7d411d8e6d9b45fab3400b4b521bbff4",
      "source": "doaj",
      "url": "https://doi.org/10.1186/s43556-026-00602-5"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2403|Immune cells in cancer",
      "subfield": "immunology"
    }
  ],
  "title": "Lysine-specific demethylase 1 (LSD1) regulates macrophage plasticity and immune checkpoint expression in colorectal liver metastases.",
  "title_text": "Lysine-specific demethylase 1 (LSD1) regulates macrophage plasticity and immune checkpoint expression in colorectal liver metastases.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T13:45:35Z",
  "url": "https://research.draconitic.com/paper/00sd5dm61gwn2",
  "venue": "Molecular biomedicine",
  "versions": []
}