Targeting a Granulocytic/Microbiome Axis Reverses Glioblastoma Progression via Intranasal Cannabidiol

Mucosal cannabidiol formulations are known regulators of the glioblastoma microenvironment, yet the underlying origin point triggering this stroma-remodeling efficacy remains entirely unknown. Here, by mapping innate cell trafficking pathways, we define a novel baseline neuro-immune-microbiome axis in orthotopic glioblastoma, characterized by diverse microbial communities, likely seeded via blood-brain barrier disruption, paired with dense infiltration of host mast cells and mature, crystalloid-containing eosinophils. Localized intranasal administration of a synthetic cannabidiol formulation achieved striking therapeutic efficacy, driving dramatic tumor regression. Mechanistically, high-throughput 16S rRNA sequencing and quantitative flow cytometry revealed this progression was subverted by taming the tumor ecosystem; cannabidiol restricted chaotic microbial diversity, selectively filtering the landscape toward Delftia and depleting Archaea, while simultaneously suppressing hyper-inflammatory host mast cell and eosinophil populations. This study builds upon established innate trafficking frameworks to present the first therapeutically targetable stromal-microbial axis in neuro-oncology.