Abstract LB076: Targeting suv39h1 epigenetic silencing to induce viral mimicry and suppress glioblastoma growth

Abstract 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, γH2AX, and phospho-RPA32T21, 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. Citation Format: Yi Sak Kim, Charles Spruck. Targeting suv39h1 epigenetic silencing to induce viral mimicry and suppress glioblastoma growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB076.