{
  "abstract": "Background: Tumor-associated macrophages (TAMs) are critical drivers in melanoma growth and metastasis orchestrating complex cellular interactions within the tumor microenvironment (TME). While the RNA-binding protein heterogeneous nuclear ribonucleoprotein C1/C2 (hnRNP C) has been linked to melanoma progression and immune evasion, its specific role in macrophage-tumor communication and TME remodeling remains poorly understood.\n\nMethods: Multiple publicly available melanoma datasets (TCGA-SKCM, GSE8401, GSE46517, and single-cell RNA sequencing) were analyzed to map hnRNP C-associated signaling pathways, and macrophage-tumor interactions. Ligand-receptor cell communication analysis was used to characterize networks within the TME. Functional studies were conducted in melanoma cell lines (Buf1379, Buf1402, Buf836) following siRNA-mediated hnRNP C knockdown using wound healing and trans-well assays to assess cell migration and invasion. Macrophage-tumor interactions were comprehensively studied via trans-well co-culture models, flow cytometry, cytokine profiling, and recombinant CXCL10 stimulation assays. Protein-level validation and clinical relevance were assessed using multicohort datasets and immunohistochemistry.\n\nResults: Elevated hnRNP C expression significantly enhanced melanoma cell migration, invasion, and epithelial-mesenchymal transition (EMT)-associated programs. Mechanistically, hnRNP C-high melanoma cells secreted increased levels of the macrophage migration inhibitory factor (MIF), which reprogrammed macrophages toward an interferon-associated TAM (IFN-TAM) phenotype. Moreover, CXCL10 via CXCR3 activation upregulated hnRNP C expression in melanoma cells establishing a bidirectional feedback loop. Single-cell transcriptomic analyses confirmed enriched MIF-mediated signaling between macrophages and melanoma cells. Spatially, this macrophage-derived CXCL10/CXCR3-hnRNP C-MIF signaling axis promoted macrophage remodeling and drove metastatic tumor states. A three-gene prognostic signature (hnRNP C-MIF-CXCR3) showed robust predictive performance across independent melanoma cohorts and strongly correlated with tumor stage, metastatic status, and overall survival. Protein-level validation confirmed elevated hnRNP C and MIF expression in melanoma tissues compared with normal skin.\n\nConclusions: This study identifies a novel macrophage-tumor signaling circuit in melanoma, wherein CXCL10/CXCR3-driven hnRNP C activation promotes MIF-mediated macrophage reprogramming and subsequent metastatic progression. The identified three-gene signature provides a clinically relevant prognostic biomarker and highlights hnRNP C as a promising therapeutic target for disrupting macrophage-driven tumor progression.",
  "abstract_shown": true,
  "affiliations": [
    "Institute of Pathology, Section Immunopathology, Martin Luther University of Halle-Wittenberg, Halle (Saale), Germany",
    "Institute of Translational Immunology, Brandenburg Medical School “Theodor Fontane”, Brandenburg an der Havel, Germany",
    "Department of Pathology, The Affiliated Hospital, Southwest Medical University, Luzhou, China"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Yuan Wang",
      "orcid": "0009-0007-1943-3286"
    },
    {
      "affs": [
        1
      ],
      "name": "Chiara Massa",
      "orcid": "0000-0001-8395-9396"
    },
    {
      "affs": [
        0
      ],
      "name": "Gowtham Chowdary Tammineni",
      "orcid": "0009-0005-5384-2118"
    },
    {
      "affs": [
        1
      ],
      "name": "Kamatchi Ulagappan"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Bo Yang",
      "orcid": "0009-0008-3935-8700"
    },
    {
      "affs": [
        0
      ],
      "name": "Dimitrios Kokoretsis",
      "orcid": "0000-0003-3158-9631"
    },
    {
      "affs": [
        0
      ],
      "name": "Yiyang Zhao",
      "orcid": "0009-0001-1070-5712"
    },
    {
      "affs": [
        1
      ],
      "name": "Karthikeyan Subbarayan"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Barbara Seliger",
      "orcid": "0000-0002-5544-4958"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/ewz0sgxyzterp.bib",
  "cited_by": 0,
  "doi": "10.1136/jitc-2026-015594",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13723903/",
  "id": "ewz0sgxyzterp",
  "issns": [
    "2051-1426"
  ],
  "landing_url": "https://doi.org/10.1136/jitc-2026-015594",
  "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",
      "2437"
    ],
    [
      "heading",
      "Immunotherapy Biomarkers"
    ],
    [
      "heading",
      "Original Research"
    ],
    [
      "openalex",
      "2403|Immune cells in cancer"
    ]
  ],
  "openalex": "W7224842274",
  "pdf_url": "https://jitc.bmj.com/content/14/10/e015594.full.pdf",
  "pmcid": "PMC13723903",
  "pmid": "42963102",
  "published": "2026-10-30",
  "publisher": "BMJ Publishing Group",
  "ris": "https://research.draconitic.com/paper/ewz0sgxyzterp.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T12:22:27Z",
      "native_id": "PMC13723903",
      "source": "pmc",
      "url": "https://doi.org/10.1136/jitc-2026-015594"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2403|Immune cells in cancer",
      "subfield": "immunology"
    }
  ],
  "title": "Enhanced tumor metastasis driven by the crosstalk between melanoma cells and tumor-associated macrophages: insights into the CXCL10/CXCR3-hnRNP C-MIF axis",
  "title_text": "Enhanced tumor metastasis driven by the crosstalk between melanoma cells and tumor-associated macrophages: insights into the CXCL10/CXCR3-hnRNP C-MIF axis",
  "type": "peer-reviewed",
  "updated_at": "2026-11-05T12:20:38Z",
  "url": "https://research.draconitic.com/paper/ewz0sgxyzterp",
  "venue": "Journal for Immunotherapy of Cancer",
  "versions": []
}