STING activation induces cytotoxic and immune responses in meningiomas via inflammatory cell death pathways
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.
Authors
- Deanna Tiek (ORCID: https://orcid.org/0000-0002-2881-7691)
- Matthew C. Tate (ORCID: https://orcid.org/0000-0002-0206-7722)
- Nishanth S. Sadagopan (ORCID: https://orcid.org/0000-0001-8083-1696)
- Ashley N. Selner (ORCID: https://orcid.org/0000-0002-5687-8862)
- Chandler Jp
- Matthew Hagan (ORCID: https://orcid.org/0000-0003-4130-3430)
- Leah K. Billingham
- Thomas Sears (ORCID: https://orcid.org/0000-0003-3834-2439)
- M. Peyre
- Caylee Silvers
- D. J. Brat
- Gavin Dunn
- Alexander H. Stegh (ORCID: https://orcid.org/0000-0003-2395-7967)
- Pouya Jamshidi (ORCID: https://orcid.org/0000-0002-2038-8589)
- Amy B. Heimberger (ORCID: https://orcid.org/0000-0002-9970-8695)
- Alicia Steffens (ORCID: https://orcid.org/0009-0005-7762-4772)
- Jared T. Ahrendsen (ORCID: https://orcid.org/0000-0002-9309-6544)
- Lisa Hurley (ORCID: https://orcid.org/0000-0001-7889-4954)
- Rahul Kishore Chaliparambil (ORCID: https://orcid.org/0000-0002-4345-5393)
- Daniel Eduardo Oyon (ORCID: https://orcid.org/0000-0003-4385-2935)
- L. Sanchez Fernandez
- Mateo Gomez (ORCID: https://orcid.org/0009-0007-3934-4985)
- Qianyi Pu
- Harrshavasan T. S. Congivaram (ORCID: https://orcid.org/0009-0003-5897-0560)
- Maciej S. Lesniak
- Michel Kalamaridès
- Hinda Najem
- Jacky Yeung
- Kathleen McCortney
- Jason M. Miska
- Abrar Choudhury
- Jawad Fares
- David R. Raleigh
- Craig M. Horbinski
- Adam M. Sonabend
- Mark W. Youngblood
- Wenxia Wang
- David M. Ashley
- Michael A. Curran
- Roger Stupp
- Gustavo Ignacio Vazquez Cervantes
- Rimas V. Lukas
- Ching Man Wai
- Peng Zhang
- Stephen T. Magill
- S. Joy Trybula
Institutions
- Northwestern University (US)
- The University of Texas MD Anderson Cancer Center (US)
- Duke University (US)
- University of California, San Francisco (US)
- Washington University in St. Louis (US)
- Yale University (US)
- Sorbonne Université (FR)
- Massachusetts General Hospital (US)
- Assistance Publique – Hôpitaux de Paris (FR)
- Northwestern University (PH)
- Jewish Hospital (US)
- Pitié-Salpêtrière Hospital (FR)
- Hope Center for Neurological Disorders (US)
- Duke Medical Center (US)
- Pediatric Brain Tumor Foundation (US)
- Neurological Surgery (US)
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Publication Details
- Journal
- Nature Communications
- Published
- 2026-02-12
- DOI
- https://doi.org/10.1038/s41467-026-69296-1
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 0.00