{
  "abstract": "Background: Chitinase-3-like-protein 1 (CHI3L1), a low-abundance protein in normal tissues, is markedly upregulated in the pancreatic tumor microenvironment (TME), where it promotes fibrosis and immune evasion. Spatial transcriptomics revealed enrichment of CHI3L1 at tumor-stroma interfaces, suggesting that cell-cell interactions regulate CHI3L1 expression.\n\nMethods: We employed 2D and 3D multicellular culture models, incorporating pancreatic cancer cells, macrophages, and pancreatic stellate cells (PSCs), to recapitulate TME-mediated CHI3L1 induction. Mechanistic insights were gained through secretome profiling, chromatin immunoprecipitation (ChIP), and methylation-specific PCR. The therapeutic potential of targeting identified axes was evaluated in an orthotopic pancreatic adenocarcinoma (PDAC) mouse model.\n\nResults: We identified CCL2, CXCL10, and SPARC as key secreted mediators during tumor-stroma crosstalk that cooperatively induced CHI3L1 expression in cancer cells via activation of NF-κB and STAT3. Specifically, inflammatory cytokines within the TME recruited macrophages to induce CCL2, which, in concert with PSCs, enhances CXCL10 and SPARC secretion. Mechanistically, NF-κB directly bound the CHI3L1 promoter, while STAT3 reduced DNA methyltransferase 1 levels, leading to promoter hypomethylation and epigenetic activation of CHI3L1. Clinically, high CHI3L1 expression correlated with the upregulated stromal CCL2, CXCL10, and SPARC levels, and the combined four-marker signature was an independent prognostic factor for both overall and disease-free survival in multivariable analysis. In vivo, blockade of the upstream stromal pathways (CCR2/CXCR3/TGFβR1) coupled with CHI3L1 neutralization reduced tumor growth and remodeled the immunosuppressive microenvironment in immunocompetent PDAC models.\n\nConclusions: Our findings uncover a cooperative multicellular signaling network that orchestrates CHI3L1 expression in cancer via transcriptional and epigenetic reprogramming. Disrupting these upstream stromal pathways concurrently with CHI3L1 neutralization was associated with reduced T-cell exhaustion, offering a promising combinatorial approach for PDAC immunotherapy.\n\nSupplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12929-026-01295-2.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Pharmacology, College of Medicine, National Cheng Kung University, No. 1, Ta-Hsueh Road, Tainan, 70101 Taiwan",
    "Department of Clinical Medical Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan",
    "Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan",
    "Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan",
    "Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan",
    "Department of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Pei-Chia Su",
      "orcid": "0009-0008-0861-9023"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Yan-Shen Shan"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Ya-Chin Hou"
    },
    {
      "affs": [
        3
      ],
      "name": "Po-Hsien Huang"
    },
    {
      "affs": [
        4
      ],
      "name": "Pao-Chi Liao"
    },
    {
      "affs": [
        0,
        5
      ],
      "name": "Yi-Ching Wang",
      "orcid": "0000-0002-7694-2067"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/0za717g5gp7dt.bib",
  "cited_by": 0,
  "doi": "10.1186/s12929-026-01295-2",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13711852/",
  "id": "0za717g5gp7dt",
  "issns": [
    "1021-7770",
    "1423-0127"
  ],
  "landing_url": "https://doi.org/10.1186/s12929-026-01295-2",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research"
    ],
    [
      "openalex",
      "2730|Pancreatic and Hepatic Oncology Research"
    ]
  ],
  "openalex": "W7223706446",
  "pdf_url": null,
  "pmcid": "PMC13711852",
  "pmid": "42934719",
  "published": "2026-10-26",
  "publisher": "BMC",
  "ris": "https://research.draconitic.com/paper/0za717g5gp7dt.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T12:22:33Z",
      "native_id": "PMC13711852",
      "source": "pmc",
      "url": "https://doi.org/10.1186/s12929-026-01295-2"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|Pancreatic and Hepatic Oncology Research",
      "subfield": "oncology"
    }
  ],
  "title": "Stromal CCL2/CXCL10/SPARC axes drive pro-tumor CHI3L1 expression for microenvironmental modulation in pancreatic cancer progression and therapeutic innovation",
  "title_text": "Stromal CCL2/CXCL10/SPARC axes drive pro-tumor CHI3L1 expression for microenvironmental modulation in pancreatic cancer progression and therapeutic innovation",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T12:22:33Z",
  "url": "https://research.draconitic.com/paper/0za717g5gp7dt",
  "venue": "Journal of Biomedical Science",
  "versions": []
}