{
  "abstract": "Background: Glioblastoma (GBM) is a highly aggressive brain tumor characterized by a profoundly immunosuppressive tumor microenvironment and limited response to immunotherapy. While interferon-γ (IFN-γ) signaling is classically associated with antitumor immunity, sustained activation of this pathway has been linked to immune dysfunction in several cancers. However, its tumor-intrinsic role in shaping immunosuppression in GBM remains poorly understood.\n\nMethods: We integrated transcriptomic and immunohistochemical analyses with clinical data from GBM patients to assess associations between IFN-γ signaling, patient survival, immune cell infiltration, and immune checkpoint expression. Genetic and pharmacological perturbation of IFN-γ signaling was performed to dissect pathway-specific effects in GBM-derived cellular models. Functional immune responses were evaluated through co-culture assays with human peripheral blood mononuclear cells (PBMCs) or isolated natural killer (NK) cells.\n\nResults: IFN-γ signaling was found significantly upregulated in GBM and associated with poor patient survival. While the activation of this pathway reduced tumor cell growth, it simultaneously induced a broad immunoregulatory transcriptional program. In turn, high IFN-γ activity was associated with increased myeloid infiltration, impaired NK and T cell cytotoxicity, and upregulation of multiple inhibitory immune checkpoints. In this context, targeting a single checkpoint, such as PD-1, failed to restore antitumor immunity. By contrast, genetic ablation of STAT1, but not IRF-1, effectively reversed IFN-γ-induced immunosuppression and restored immune effector function, identifying STAT1 as a central mediator of this phenotype. Pharmacological inhibition of JAK1/2 recapitulated STAT1 loss in vitro, suppressing IFN-γ-dependent immune inhibitory programs and restoring cytotoxic activity.\n\nConclusions: These findings demonstrated that tumor IFN-γ signaling drives a STAT1-dependent immunosuppressive state in GBM that functionally impairs antitumor immunity. Our study defines a dominant regulatory axis linking IFN-γ signaling to immune escape mechanisms in GBM and provides a mechanistic framework for future studies exploring therapeutic modulation of this pathway to enhance immunotherapy response.\n\nSupplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12916-026-05128-9.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Functional Biology, Immunology, University of Oviedo, Oviedo, 33006 Spain",
    "Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, 33006 Spain",
    "Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, 33011 Spain",
    "Biobank of Principado de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, 33011 Spain",
    "Department of Pathology, Hospital Universitario Central de Asturias, Oviedo, 33011 Spain",
    "Spanish Biomedical Research Network in Cancer (CIBERONC), Instituto de Salud Carlos III, Madrid, 28029 Spain"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Candelaria Aguilar-García"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Alejandra Martínez-Pérez"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Christian Sordo-Bahamonde"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Rocío Granda-Díaz"
    },
    {
      "affs": [
        3,
        4
      ],
      "name": "Iván Fernández-Vega"
    },
    {
      "affs": [
        1,
        2,
        5
      ],
      "name": "Juana María García-Pedrero"
    },
    {
      "affs": [
        1,
        2,
        5
      ],
      "name": "Francisco Hermida-Prado"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Segundo González",
      "orcid": "0000-0003-4631-9255"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/b4tbvzwzef8h2.bib",
  "cited_by": 0,
  "doi": "10.1186/s12916-026-05128-9",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13741721/",
  "id": "b4tbvzwzef8h2",
  "issns": [
    "1741-7015"
  ],
  "landing_url": "https://doi.org/10.1186/s12916-026-05128-9",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research"
    ],
    [
      "openalex",
      "2730|Glioma Diagnosis and Treatment"
    ]
  ],
  "openalex": "W7202081574",
  "pdf_url": null,
  "pmcid": "PMC13741721",
  "pmid": "42989284",
  "published": "2026-08-10",
  "publisher": "BMC",
  "ris": "https://research.draconitic.com/paper/b4tbvzwzef8h2.ris",
  "sources": [
    {
      "first_seen": "2026-11-10T12:22:43Z",
      "native_id": "PMC13741721",
      "source": "pmc",
      "url": "https://doi.org/10.1186/s12916-026-05128-9"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|Glioma Diagnosis and Treatment",
      "subfield": "oncology"
    }
  ],
  "title": "IFN-γ signaling drives multiple immunosuppressive pathways and poor clinical outcome in glioblastoma",
  "title_text": "IFN-γ signaling drives multiple immunosuppressive pathways and poor clinical outcome in glioblastoma",
  "type": "peer-reviewed",
  "updated_at": "2026-11-10T12:22:43Z",
  "url": "https://research.draconitic.com/paper/b4tbvzwzef8h2",
  "venue": "BMC Medicine",
  "versions": []
}