cGAS-STING agonists in preclinical glioblastoma animal models: a systematic review of tumor microenvironment modulation and survival outcomes

Clinical Snapshot

Key Findings

• P Value: Not provided

• Effect Size: Not quantified - descriptive synthesis only

• Primary Outcome: Increased CD8+ T-cell and NK cell infiltration with macrophage repolarization toward pro-inflammatory phenotypes

• Nnt Or Sensitivity: Several studies reported prolonged survival with long-term tumor clearance in select models

• Confidence Interval: Not provided

Clinical Application

Multiple delivery methods demonstrated (intracranial injection, hydrogels, nanoparticles) but clinical translation remains challenging No direct relevance to current Australian practice; TGA approval would require successful clinical trials following preclinical promise Currently limited to research settings; not applicable to clinical practice

Abstract

BACKGROUND/PURPOSE: Glioblastoma (GBM) is characterized by an immunosuppressive tumor microenvironment and poor responsiveness to immune checkpoint blockade, driving interest in cGAS-STING pathway activation to stimulate antitumor immunity. We performed a systematic review of preclinical in vivo studies evaluating STING agonists in glioblastoma, with emphasis on immune microenvironment effects and survival outcomes. METHODS: A systematic review of PubMed, Cochrane, and Embase was conducted through February 2025 following PRISMA guidelines. Studies were included if they evaluated STING agonists in live animal models of GBM and reported survival outcomes or tumor microenvironment changes. Two reviewers independently screened studies and extracted data. Risk of bias was assessed qualitatively based on study design and reporting characteristics. Given heterogeneity in models, treatments, and outcomes, results were synthesized descriptively. RESULTS: Fourteen studies met the inclusion criteria, spanning synthetic and natural cyclic dinucleotides and non-cyclic STING agonists. Across diverse delivery methods, including intracranial injection, hydrogels, and nanoparticle systems, STING agonists were associated with increased CD8 + T-cell and NK cell infiltration and repolarization of tumor-associated macrophages toward pro-inflammatory phenotypes. Several studies reported prolonged survival, including long-term tumor clearance in select models. Combination therapies with immune checkpoint inhibitors or radiotherapy showed synergistic effects in some studies. CONCLUSIONS: STING agonists can enhance anti-tumor immune responses and prolong survival in preclinical GBM models by promoting cytotoxic lymphocyte recruitment and remodeling the tumor-associated myeloid landscape. However, translation remains challenging due to limitations of current models, the limited clinical traction STING modulation has thus far achieved in other cancer types, incomplete understanding of cell-type-specific STING activation in the brain, and the possibility that sustained STING signaling may drive maladaptive inflammation rather than durable antitumor immunity.

References

1. 1.Sampath, S. G., Tang, A. J., Chen, A. X., Viswanathan, A., Izima, C., Manriquez, A. H., Dadario, N. B., Winans, N., Amini, M., Rolfe, N., Adapa, A. R., Argenziano, M. G., Sperring, C. P., Neira, J. A., Lei, L., Canoll, P., & Bruce, J. N. (2026). cGAS-STING agonists in preclinical glioblastoma animal models: a systematic review of tumor microenvironment modulation and survival outcomes. Journal of Neuro-Oncology. https://doi.org/10.1016/j.celrep.2022.111647