Review of STING agonists for high-grade and diffuse midline glioma discusses systemic toxicity and delivery constraints.

High-grade gliomas, including diffuse midline glioma (DMG), remain some of the most aggressive and treatment-resistant brain tumours, largely due to their diffuse growth, inoperability, and profoundly immunosuppressive tumour microenvironments (TMEs). The stimulator of interferon genes (STING) pathway has emerged as a promising immunotherapeutic target, capable of activating type I interferon responses and bridging innate and adaptive immunity. This review explores the dual role of STING in tumour immunity and TME modulation, examining both canonical and non-canonical signalling pathways. We summarise advances in STING agonist development, including cyclic dinucleotides, synthetic non-cyclic dinucleotides, and metal-based compounds, and critically assess their translational potential in the context of brain tumours. While preclinical studies demonstrate robust antitumour efficacy, clinical translation remains limited by systemic toxicity, delivery constraints, and variability in STING expression across glioma subtypes. We hence offer insights into novel drug delivery approaches such as nanoparticles, liposomes, hydrogels, and focused ultrasound for overcoming the key challenges of bioavailability and blood-brain barrier penetration of the agonists. We also highlight emerging combinatorial strategies—particularly checkpoint inhibitors and epigenetic modulators—as essential to enhancing therapeutic outcomes; an outlook not previously explored for brain malignancies. Overall, we conclude that STING agonism offers a compelling strategy for immunomodulation in gliomas, but further optimisation of delivery, safety, and mechanistic understanding is crucial for successful clinical application.