ArticleJournal for immunotherapy of cancer2025
EZH2 inhibition and 5-azacytidine enhance antitumor immunity in PTEN-deficient glioblastoma by activation viral mimicry response.
Article in Journal for immunotherapy of cancer, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Targeting the DNA Damage Response in Cancer.MedComm · 2026Review
- Tumour-associated dsRNA accumulation and innate immune activation: mechanistic basis and therapeutic strategies.EBioMedicine · 2026Review
- Viral mimicry escape as a necessary feature of malignant transformation.Nature reviews. Cancer · 2026Review
- Enhancer of Zeste Homolog 2 (EZH2): From Glioblastoma Biology to Potential Epigenetic Therapy.International journal of molecular sciences · 2026Review
- Overexpression of EZH2 is associated with clinicopathological parameters and poor prognosis in gliomas.Oncology letters · 2026Article
- KRTCAP2 accelerates malignant progression through modulating tumor cell function and M2 macrophage infiltration in glioma.Frontiers in immunology · 2026Article
- Activation of endogenous retroviruses in tumor cells and their immunomodulatory mechanisms: from molecular basis to clinical translation.Frontiers in oncology · 2026Review
- BATF2 is a glutamine-responsive tumour suppressor required for type-I interferon-dependent anti-tumour immunity.Nature communications · 2025Article
- Endogenous retroviruses in aging and cancer: from genomic defense to oncogenic activation.Mobile DNA · 2025Review
- Niche-specific epigenetic interventions in the spatially heterogeneous glioblastoma microenvironmental landscape: strategies for radiotherapy enhancement.Frontiers in molecular biosciences · 2025Review
- Epigenetic crosstalk between stem cells and tumors: mechanisms and emerging perspectives.American journal of stem cells · 2025Review
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Authors and funding
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Funding
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Abstract
backgroundPTEN-deficient glioblastoma (GBM) is characterized by an immunosuppressive tumor microenvironment (TME), therapeutic resistance, and poor prognosis. Emerging evidence suggests that dysregulation of the endogenous retrovirus (ERV)-MAVS-IFN pathway may contribute to immune evasion in cancer, but its role in PTEN-deficient GBM remains unclear.
methodsUsing flow cytometry and single-cell RNA sequencing, we analyzed the immune landscape of PTEN-deficient GBM. We evaluated the effects of 5-azacytidine (5-AZA) monotherapy and its combination with EZH2 inhibition (EZH2i) on ERV reactivation, type I interferon (IFN) responses, and TME remodeling. Mechanistic studies focused on H3K27me3-mediated epigenetic regulation of ERV expression.
resultsWe found that PTEN deficiency suppresses type I IFN responses by impairing viral mimicry through dysregulation of the ERV-MAVS-IFN pathway, thereby sustaining an immunosuppressive TME. While 5-AZA alone failed to reactivate ERVs or overcome therapeutic resistance, combining it with EZH2i synergistically restored robust type I IFN signaling. This combination therapy reduced H3K27me3 levels, promoting ERV transcriptional activation and enhancing 5-AZA-induced viral mimicry. Consequently, the dual treatment reprogrammed the TME to boost antitumor immunity and suppress tumor progression.
conclusionsOur study demonstrates that PTEN-deficient GBM evades immune surveillance by suppressing the ERV-MAVS-IFN axis. The combination of EZH2i and 5-AZA overcomes this resistance by epigenetically reactivating viral mimicry, offering a promising therapeutic strategy to enhance antitumor immunity and improve outcomes in patients with PTEN-deficient GBM.
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