STING activation induces cytotoxic and immune responses in meningiomas via inflammatory cell death pathways

TL;DR

This study shows that activating the STING pathway with 8803 can kill meningioma tumor cells and boost immune responses, offering a potential new treatment for these brain tumors.

Contribution

The study demonstrates that STING agonism induces inflammatory cell death and immune activation in meningiomas, suggesting a novel therapeutic strategy.

Findings

STING activation with 8803 causes tumor cell death through gasdermin D-mediated inflammatory pathways.

8803 treatment activates macrophages and increases matrix metalloproteinase production, degrading collagen in the tumor microenvironment.

Preclinical models show improved survival with 8803, due to immune infiltration and reduced tumor-mediated immune suppression.

Abstract

Meningiomas are common tumors of the central nervous system that are typically treated with surgery or radiation, but lack established systemic therapies. Activation of the stimulator of interferon genes pathway with an agonist such as 8803 can trigger anti-tumor immune responses. Using integrated molecular approaches, here we show that this pathway is targetable in both neoplastic and immune populations within the meningioma microenvironment. Meningioma tumor cells exhibit promoter hypomethylation and increased chromatin accessibility of the STING genomic locus, associated with robust expression of this gene. Treatment of diverse patient meningiomas ex vivo with 8803 induces direct tumor cytotoxicity through inflammatory cell death pathways, including induction of gasdermin D membrane pore formation. Release of necrotic tumor debris triggered by 8803 activates macrophages and upregulates matrix metalloproteinase production, facilitating degradation of extra-cellular collagen. Injection of preclinical meningiomas with 8803 induces survival benefits, including in an immunocompetent orthotopic setting, through remodeling of the tumor microenvironment, immune infiltration, and downregulation of tumor-mediated immune suppression, thereby nominating 8803 for treatment consideration in meningiomas.

Meningiomas are common brain tumors with variable behavior. This study reveals high STING expression across multiple cell types in the meningioma microenvironment. STING agonism triggers tumor cell death via programmed necrosis and pyroptosis, enhancing survival in preclinical models.

Figures