Abstract A003: Chronic cGAS–STING activation reprograms glioblastoma-associated macrophages toward immunosuppression in hypoxic tumor niches

Abstract The cGAS–STING pathway in macrophages is essential for converting DNA damage into antitumor immune responses. Cytosolic double-stranded DNA is sensed by cGAS to generate cGAMP, the endogenous agonist for STING, whose activation stimulates interferon responses. However, sustained STING pathway engagement may paradoxically promote immune suppression. Whether glioblastoma (GBM)-associated macrophages adopt distinct "acute" versus "chronic" STING activation states and how these states relate to spatial tumor niches remains unclear. We modeled acute and chronic STING signaling in macrophages by comparing single-dose versus repeated cGAMP stimulation and characterized the resulting transcriptional and metabolic programs. As expected, acute STING activation induced a canonical interferon-driven inflammatory response. In contrast, repeated stimulation produced a functionally exhausted state marked by loss of interferon signaling, upregulation of immunosuppressive markers, and metabolic reprogramming toward reduced oxidative phosphorylation. Projection of these gene signatures onto bulk patient data (TCGA-GBM and IvyGAP) revealed that chronic STING activation programs were enriched in hypoxic tumor regions, correlated with T-cell exhaustion, and were associated with significantly worse survival. Spatial transcriptomic analysis further demonstrated that chronic STING signatures localized to the hypoxic tumor core, whereas acute inflammatory signatures predominate at the invasive tumor edge. Together, these findings show that while acute STING signaling is inflammatory, sustained pathway engagement promotes macrophage immunosuppression in hypoxic GBM niches, underscoring the need to optimize timing and duration of STING agonist and genotoxic therapy to avoid adaptive immunoresistance. Citation Format: Sebastian Ouyang, Virginia Wertman, Michael Brown, Matthew Waitkus, Justin Low, David Ashley. Chronic cGAS–STING activation reprograms glioblastoma-associated macrophages toward immunosuppression in hypoxic tumor niches [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr A003.