Context-dependent roles of cGAS-STING signaling in glioblastoma: Therapeutic resistance, drug delivery, and heterogeneity-informed translation.

Abstract

Glioblastoma (GBM) is an aggressive primary brain tumor with poor prognosis, profound spatial and cellular heterogeneity, and a highly immunosuppressive microenvironment. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a central cytosolic DNA-sensing axis that activates innate immune responses, largely through the induction of type I interferons and inflammatory signaling. Increasing evidence indicates that the role of cGAS-STING signaling in GBM is highly context dependent. Acute activation, particularly in immune cells, may enhance antitumor immunity by promoting interferon-driven immune activation and facilitating tumor immune recognition. In contrast, chronic, dysregulated, or tumor-intrinsic activation may promote NF-κB-mediated inflammation, immune evasion, genomic instability-associated adaptation, and therapeutic resistance. In this review, we summarize the canonical biology of the cGAS-STING pathway, its regulatory and escape mechanisms, its distinctive features in the central nervous system, and its expression and functional relevance in GBM. We further discuss STING-targeted therapeutic strategies, including STING agonist monotherapy, drug delivery systems, and rational combination approaches, and synthesize current preclinical and clinical evidence supporting their application in GBM. Finally, we highlight major translational challenges, including blood-brain barrier penetration, cell-type-specific pathway activation, treatment-induced pathway remodeling, and biomarker selection, and propose a heterogeneity-informed framework for patient stratification and precision immunotherapy development in GBM.