IFN-γ signaling drives multiple immunosuppressive pathways and poor clinical outcome in glioblastoma
6 affiliations
- 1Department of Functional Biology, Immunology, University of Oviedo, Oviedo, 33006 Spain
- 2Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, 33006 Spain
- 3Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, 33011 Spain
- 4Biobank of Principado de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, 33011 Spain
- 5Department of Pathology, Hospital Universitario Central de Asturias, Oviedo, 33011 Spain
- 6Spanish Biomedical Research Network in Cancer (CIBERONC), Instituto de Salud Carlos III, Madrid, 28029 Spain
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.
Methods: 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.
Results: 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.
Conclusions: 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.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12916-026-05128-9.
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BibTeX
@article{aguilargarcia2026ifnγ,
title = {{IFN-γ signaling drives multiple immunosuppressive pathways and poor clinical outcome in glioblastoma}},
author = {Candelaria Aguilar-García and Alejandra Martínez-Pérez and Christian Sordo-Bahamonde and Rocío Granda-Díaz and Iván Fernández-Vega and Juana María García-Pedrero and Francisco Hermida-Prado and Segundo González},
journal = {BMC Medicine},
year = {2026},
month = aug,
doi = {10.1186/s12916-026-05128-9},
url = {https://doi.org/10.1186/s12916-026-05128-9},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - IFN-γ signaling drives multiple immunosuppressive pathways and poor clinical outcome in glioblastoma
AU - Candelaria Aguilar-García
AU - Alejandra Martínez-Pérez
AU - Christian Sordo-Bahamonde
AU - Rocío Granda-Díaz
AU - Iván Fernández-Vega
AU - Juana María García-Pedrero
AU - Francisco Hermida-Prado
AU - Segundo González
PY - 2026
DA - 2026/08/10
JO - BMC Medicine
DO - 10.1186/s12916-026-05128-9
UR - https://doi.org/10.1186/s12916-026-05128-9
AB - 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. Methods: 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. Results: 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. Conclusions: 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. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12916-026-05128-9.
SN - 1741-7015
ER -