Targeting suv39h1 epigenetic silencing to induce viral mimicry and suppress glioblastoma growth

Glioblastoma (GBM) remains one of the most aggressive and treatment-resistant brain tumors. Epigenetic silencing of transposable elements (TEs) by histone methyltransferases such as SUV39H1 suppresses innate immune activation by preventing viral mimicry. In this study, we investigated whether pharmacological or genetic inhibition of SUV39H1 could reactivate silenced retroelements and stimulate anti-tumor immunity in GBM. We demonstrate that SUV39H1 inhibition in murine glioma models (CT2A and 005-GSC) leads to a robust accumulation of cytosolic double-stranded RNA (dsRNA), upregulation of endogenous retroelements including LINE-1, and activation of interferon-stimulated genes (ISGs), all hallmarks of viral mimicry induction. These molecular changes were accompanied by elevated replication stress markers, including increased cytosolic dsDNA, gammaH2AX, and phospho-RPA32 T21 , indicating a dual mechanism of anti-tumor activity. In vivo, SUV39H1 treatment with the small-molecule inhibitor F5446 significantly reduced tumor growth and extended survival in orthotopic GBM models. Immunofluorescence analysis of treated GBM tumors revealed increased LINE-1 ORF2 protein expression and a shift in tumor-resident microglia toward a pro-inflammatory phenotype, characterized by increased CD86⁺ microglia and reduced ARG1⁺ microglia, suggesting tumor microenvironment remodeling driven by epigenetic reprogramming. Together, our findings position SUV39H1 as a central epigenetic barrier that represses immune-stimulatory signals in glioblastoma. Its inhibition stimulates viral mimicry and induces replication stress, presenting a promising strategy for sensitizing GBM to immunotherapy. This study paves the way for future combination therapies integrating epigenetic drugs with immune checkpoint inhibitors to overcome immune evasion in glioblastoma.