Abstract 2900: Activation of the cGAS-STING signaling pathway as an immunotherapeutic approach to glioblastoma

Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor, characterized by rapid progression, resistance to therapy, and a highly immunosuppressive tumor microenvironment (TME). By sensing and reacting to cytosolic DNA, the cGAS-STING signaling pathway plays a critical role in innate immune defense, producing type I interferons and pro-inflammatory cytokines. In GBM, STING expression is frequently downregulated, contributing to tumor immune evasion. We set out to evaluate the potential of stimulating cGAS-STING signaling as a strategy to modulate the TME and provoke anti-tumor immunity in preclinical models of GBM based on murine GBM stem-like cell lines (005, NF53, C3, RIG) that are driven by TP53 loss and HrasV12. We found heterogeneous baseline expression levels of cGAS-STING components in these murine GBM cells, analogous to our observation in human patient-derived GBM cells. Despite this variability, murine GBM cells consistently responded to exposure to STING agonist ADU-S100 with transient IRF3 phosphorylation and robust induction of type I interferons (IFN-β) and chemokines (CXCL10, CCL5). In vivo, intratumoral injection of ADU-S100 (50 micrograms) mediated therapeutic efficacy against murine orthotopic GBM in C57BL/6 mice as it resulted in significant survival extension including long-term survival. This was achieved despite apparent ADU-S100-elicited, acute and transient body weight loss. Rechallenge of the same GBM cells in the contralateral hemisphere in long-term survivors was rejected, indicative of immune memory. These findings support pharmacological cGAS-STING activation as a strategy to counter GBM-driven immune suppression and a promising immunotherapeutic approach to this deadly brain tumor. Citation Format: Louise Leparc, Judit Sanchez Gil, Hiroaki Wakimoto. Activation of the cGAS-STING signaling pathway as an immunotherapeutic approach to glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2900.