{
  "abstract": "Macrophages in colorectal cancer (CRC) are predominantly derived from monocytes, yet the mechanisms by which the tumor microenvironment (TME) regulates their differentiation dynamics and phenotypic commitment remains poorly defined. Although we previously identified ANKRD22 as a macrophage immunomodulator, the regulation of ANKRD22 by the TME and its temporal impact on monocyte‒macrophage differentiation are still unclear. We used untargeted metabolomics and cytokine microarrays to identify metabolites and cytokines from CRC cell supernatants that suppress ANKRD22 expression in macrophages. Immune infiltration in tumors was evaluated using cytometry by time-of-flight. The effects of ANKRD22 downregulation on monocyte-to-macrophage differentiation were investigated using scRNA-seq, scATAC-seq, and multiplex immunofluorescence staining. CRC cell-derived metabolites and cytokines downregulated ANKRD22 expression in macrophages via the p38 MAPK/MAX pathway. Ankrd22-deficient macrophages accelerated subcutaneous tumor growth in mice, promoting the expansion of immunosuppressive CD206⁺CD163⁺ macrophage subsets and decreasing the number of CD8⁺CD44⁺CD62L- effector T cells. ANKRD22 downregulation delayed macrophage differentiation and maturation while increasing monocyte recruitment. Mechanistically, ANKRD22 suppression reduced the level of intracellular fatty acids, which in turn activated the Notch4/HES1 pathway, leading to differentiation arrest and immunosuppressive polarization. This process involved a newly identified early-differentiation immunosuppressive CD9⁺CD127⁺ macrophage subset within the TME. The combined pharmacological inhibition of Notch and long-acting IL-7 expression reversed these phenotypes, attenuated tumor growth, and diminished the CD9⁺CD127⁺ population. ANKRD22 downregulation reprograms fatty acid metabolism to activate the Notch4/HES1 pathway, promoting immunosuppressive macrophage polarization. ANKRD22 is a key regulator of macrophage plasticity and a promising therapeutic target for reprogramming the immunosuppressive TME in CRC.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Gastroenterology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China.",
    "Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Bin Yang"
    },
    {
      "affs": [
        0
      ],
      "name": "Liang Hong"
    },
    {
      "affs": [
        0
      ],
      "name": "Shuyu Li"
    },
    {
      "affs": [
        0
      ],
      "name": "Ruoxi Li"
    },
    {
      "affs": [
        0
      ],
      "name": "Rui Wang"
    },
    {
      "affs": [
        1
      ],
      "name": "Sheng Yao"
    },
    {
      "affs": [
        0
      ],
      "name": "Tianhui Pan"
    },
    {
      "affs": [
        0
      ],
      "name": "Dandan Zhong"
    },
    {
      "affs": [
        0
      ],
      "name": "Caihua Wang"
    },
    {
      "affs": [
        0
      ],
      "name": "Yongliang Zhu",
      "orcid": "0000-0001-7450-885X"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/1q1qkepxd11qe.bib",
  "cited_by": 0,
  "doi": "10.2147/itt.s642879",
  "fulltext_url": "https://europepmc.org/articles/PMC13744201",
  "id": "1q1qkepxd11qe",
  "issns": [
    "2253-1556"
  ],
  "landing_url": "https://europepmc.org/article/MED/42999633",
  "language": "eng",
  "licence": "CC-BY-NC",
  "licence_label": "CC BY-NC",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2403|Immune cells in cancer"
    ]
  ],
  "openalex": "W7225203135",
  "pdf_url": "https://europepmc.org/articles/PMC13744201?pdf=render",
  "pmcid": "PMC13744201",
  "pmid": "42999633",
  "published": "2026-11-03",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/1q1qkepxd11qe.ris",
  "sources": [
    {
      "first_seen": "2026-11-09T15:20:34Z",
      "native_id": "MED:42999633",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42999633"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2403|Immune cells in cancer",
      "subfield": "immunology"
    }
  ],
  "title": "ANKRD22 Downregulation Reprograms Lipid Metabolism to Activate the Notch/Hes1 Pathway, Driving Immunosuppressive Macrophage Polarization in Colorectal Cancer.",
  "title_text": "ANKRD22 Downregulation Reprograms Lipid Metabolism to Activate the Notch/Hes1 Pathway, Driving Immunosuppressive Macrophage Polarization in Colorectal Cancer.",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T15:20:34Z",
  "url": "https://research.draconitic.com/paper/1q1qkepxd11qe",
  "venue": "ImmunoTargets and therapy",
  "versions": []
}