STING-induced programmed necrosis modulates the collagen-rich immunosuppressive microenvironment in meningiomas [RNA-seq]

ABSTRACT: Up to one-quarter of meningiomas recur within five years of resection; however, there are currently no established adjuvant therapies for tumors that are intractable to surgery and radiation. Using integrated epigenetic and transcriptional profiling, we identify widespread expression of STING across multiple cell populations within the meningioma microenvironment, associated with increased chromatin accessibility in neoplastic cells and promoter hypomethylation. Ex vivo single-cell suspensions of resected human meningiomas treated with the STING agonist 8803 induced direct cytotoxicity within 72 hours, including even in the absence of CD45+ immune cells. Pharmacologic inhibitors and RNA-sequencing revealed the association of programmed necrotic cell death pathways that require reactive oxygen species production with STING agonist8803 efficacy, which also required reactive oxygen species production. Proteolytic maturation of the pore-forming protein gasdermin D (GSDMD) on meningioma cancer cells contributeds to 8803-induced cytotoxicity, and the suggested release of pro-inflammatory damage-associated molecular pattern molecules that further upon 8803-induced cytotoxicity, which further potentiatedpotentiates STING activation of innate immune cell activation and responses through toll-like receptors activation. Across four different preclinical murine meningioma models, 8803 reduced tumormeningioma volume, and survival significantly increased survival was significantly improved after treatment of across three orthotopic tumorsmodels. These therapeutic effects arewere Treatment with 8803 across multiple pre-clinical orthotopic meningioma models exhibited improved survival associated with marked immunological tumor infiltration and cytotoxicity, tumor stromal remodeling through macrophage elaborated metalloproteinases, and downregulation of the TIM3 and LAIR1 widespread cytotoxicity and immunologic infiltration during the therapeutic window, including down-regulation of severalthe dominant mechanisms of meningioma-mediated immune suppression. , such as TIM3 and LAIR1, alongside the LAIR ligand collagen through macrophage elaborated MMP production. Our results reveal widespread synergistic expression of STING in neoplastic and myeloid populations of meningiomas, identify novel mechanisms of STING signalingcytotoxicity inthrough tumor cells, andsuggest a role for STING activation in degradation of collagen-rich tumor microenvironments the impact on the extracellular matrix, and clarify a new treatment indication for the STING agonist 8803.

ORGANISM(S): Homo sapiens

PROVIDER: GSE297637 | GEO | 2025/12/02

REPOSITORIES: GEO