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Transcriptomic profiling of STING-agonist-sensitive and resistant glioblastoma cells under acute diABZI stimulation and chronic selection

ABSTRACT: Glioblastoma (GBM) exhibits profound therapeutic resistance and an immunosuppressive tumor microenvironment. The cGAS–STING pathway is an attractive target, yet sustained pathway activation can trigger adaptive escape. To define tumor-intrinsic adaptations to STING agonists, we generated an isogenic model using H4 GBM cells: (i) parental H4 treated with vehicle (DMSO, 6 h), (ii) parental H4 challenged acutely with diABZI (1 uM, 6 h), and (iii) a resistant subline (H4-R) derived by chronic diABZI dose escalation (up to 20 uM for >2 months) and harvested drug-free. Poly(A) RNA-seq (NovaSeq 6000, paired-end 150 bp) was performed in biological triplicates. Acute STING activation in parental cells induced a stereotypic interferon/chemokine program centered on CXCL10 together with apoptosis-related genes, whereas H4-R showed suppression of DNA-sensing/STING outputs and a shift toward hypoxia/ECM signatures. In functional assays, CXCL10 neutralization reduced STING-agonist efficacy, while recombinant CXCL10 restored responses. Processed results are provided in GEO; raw FASTQ files are in SRA under the linked BioProject. This dataset enables reuse for benchmarking STING biology, chemokine signaling, and resistance mechanisms in GBM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE305239 | GEO | 2026/09/01

REPOSITORIES: GEO

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Project description:Temozolomide (TMZ) is an important first-line treatment for glioblastoma (GBM), but there are limitations to TMZ response in terms of durability and dependence on the promoter methylation status of the DNA repair gene O6-methylguanine DNA methyltransferase (MGMT). MGMT-promoter-hypermethylated (MGMT-M) GBMs are more sensitive to TMZ than MGMT-promoter-hypomethylated (MGMT-UM) GBMs. Moreover, TMZ resistance is inevitable even in TMZ-sensitive MGMT-M GBMs. Hence, epigenetic reprogramming strategies are desperately needed in order to enhance TMZ response in both MGMT-M and MGMT-UM GBMs. In this study, we present novel evidence that the epigenetic reactivation of Tumor Suppressor Candidate 3 (TUSC3) can reprogram sensitivity of GBM stem cells (GSCs) to TMZ irrespective of MGMT promoter methylation status. Interrogation of TCGA patient GBM datasets confirmed TUSC3 promoter regulation of TUSC3 expression and also revealed a strong positive correlation between TUSC3 expression and GBM patient survival. Using a combination of loss-of-function, gain-of-function and rescue studies, we demonstrate that TUSC3 reactivation is associated with enhanced TMZ response in both MGMT-M and MGMT-UM GSCs. Further, we provide novel evidence that the demethylating agent 5-Azacitidine (5-Aza) reactivates TUSC3 expression in MGMT-M GSCs, whereas the combination of 5-Aza and MGMT inhibitor Lomeguatrib is necessary for TUSC3 reactivation in MGMT-UM GSCs. Lastly, we propose a pharmacological epigenetic reactivation strategy involving TUSC3 that leads to significantly prolonged survival in MGMT-M and MGMT-UM orthotopic GSCs models. Collectively, our findings provide a framework and rationale to further explore TUSC3-mediated epigenetic reprogramming strategies that could enhance TMZ sensitivity and outcomes in GBM. Mechanistic and translational evidence gained from such studies could contribute towards optimal design of impactful trials for MGMT-UM GBMs that currently do not have good treatment options.

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Transcriptomic profiling of STING-agonist-sensitive and resistant glioblastoma cells under acute diABZI stimulation and chronic selection

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