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Proinflammatory macrophage secretome enhances temozolomide sensitivity in glioblastoma via pSTAT3-mediated downregulation of DNA repair enzymes

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dc.contributor.authorLópez-López, Susana
dc.contributor.authorCastro-Robles, Beatriz
dc.contributor.authorGarcía-Flores, Natalia
dc.contributor.authorDíaz-Guerra, María José M.
dc.contributor.authorArias-Salazar, Lourdes
dc.contributor.authorSandoval, Hernán
dc.contributor.authorGarcía Pérez, Daniel
dc.contributor.authorKlein-Zampaña, Christoph J.
dc.contributor.authorBarbella-Aponte, Rosa A.
dc.contributor.authorSegura, Tomás
dc.contributor.authorSerrano-Heras, Gemma
dc.contributor.departmentFarmacología
dc.contributor.otherFacultad de Farmacia
dc.date.accessioned2026-02-24T09:31:16Z
dc.date.available2026-02-24T09:31:16Z
dc.date.copyright© 2025 The Author(s)
dc.date.issued2025-11-06
dc.description.abstractThe mechanisms by which tumor-associated macrophages, key components of the glioblastoma (GBM) microenvironment, impair chemotherapy efficacy remain poorly understood. Resistance to temozolomide (TMZ), the standard chemotherapeutic agent for GBM, is associated with poor prognosis due to efficient DNA repair mechanisms. While low expression of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) has been linked to improved TMZ response, our previous findings suggest that N-methylpurine-DNA glycosylase (MPG) may also contribute to chemoresistance in GBM. Here, we report for the first time that conditioned medium from pro-inflammatory macrophages (CM-M1) enhances TMZ cytotoxicity by suppressing STAT3 phosphorylation, resulting in decreased MGMT and MPG expression in GBM cells. Proteomic profiling of CM-M1 revealed a unique, cytokine-rich secretome that may promote STAT1 activation, thereby inhibiting pSTAT3 and reducing DNA repair enzymes levels. Clinically, elevated MGMT and MPG protein levels were associated with increased pSTAT3 in our GBM patient cohort, and analysis of the TCGA database further showed that their combined overexpression correlates with significantly reduced progression-free survival. Gene silencing experiments confirmed the contribution of both enzymes to TMZ resistance, with dual knockdown producing a synergistic sensitizing effect. These findings uncover a novel mechanism of macrophage secretome–mediated chemoresistance and support the development of M1-based strategies to improve TMZ efficacy in GBM.
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dc.identifier.citationLópez-López S, Castro-Robles B, García-Flores N, Díaz-Guerra MJM, Arias-Salazar L, Sandoval H, García-Pérez D, Klein-Zampaña CJ, Barbella-Aponte RA, Segura T, Serrano-Heras G. Proinflammatory macrophage secretome enhances temozolomide sensitivity in glioblastoma via pSTAT3-mediated downregulation of DNA repair enzymes. Sci Rep. 2025 Nov 6;15(1):38875. doi: 10.1038/s41598-025-22674-z
dc.identifier.doihttps://doi.org/10.1038/s41598-025-22674-z
dc.identifier.eissn2045-2322
dc.identifier.urihttp://hdl.handle.net/10201/211721
dc.languageeng
dc.publisherNature Research
dc.relationSusana López-López was the recipient of a contract funded by Fundación Hospital Nacional de Parapléjicos- Instituto de Investigación Sanitaria de Castilla-La Mancha (IDISCAM), Castilla-La Mancha, Spain, during the years 2021 and 2022. Gemma Serrano-Heras is the recipient of a contract funded by the grant awarded to the project ´ Refuerzo de la actividad investigadora de Castilla-La Mancha (EMER)´ (Fundación Hospital Nacional de Parapléjicos- Instituto de Investigación Sanitaria de Castilla-La Mancha (IDISCAM), Castilla-La Mancha, Spain).
dc.relation.publisherversionhttps://www.nature.com/articles/s41598-025-22674-z
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectChemoresistance
dc.subjectProinflammatory macrophage
dc.subjectSecretome
dc.subjectDNA repair enzymes
dc.subjectMPG
dc.subjectGlioblastoma (GBM)
dc.subject.odsNo relacionado con ningún objetivo de desarrollo sostenible
dc.titleProinflammatory macrophage secretome enhances temozolomide sensitivity in glioblastoma via pSTAT3-mediated downregulation of DNA repair enzymes
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
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relation.isAuthorOfPublication.latestForDiscovery2f2500a1-1b27-4420-820c-db8c16e79afd
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