Convection-enhanced delivery of dexamethasone in glioma models suppresses myeloid inflammation while avoiding systemic toxicities

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Abstract

Dexamethasone is widely used to control cerebral edema and inflammation in glioblastoma, but its benefits are limited by systemic toxicities and adverse prognostic associations. We evaluated local administration of dexamethasone via convection-enhanced delivery (CED) to maximize intratumoral anti-inflammatory effects by increasing local corticosteroid exposure while minimizing systemic exposure. In two glioma mouse models, continuous intraparenchymal infusion of dexamethasone was well tolerated with no adverse effects. Pharmacokinetic analyses supported preferential intratumoral distribution and reduced systemic exposure with CED compared with systemic dosing. Single-nucleus RNA sequencing (snRNA-seq) and immunohistochemistry showed attenuation of glioma-associated inflammation with downregulation of reactive microglial/macrophage programs and reduced tumor-infiltrating myeloid cells with a morphology consistent with a less activated state. Experiments in human induced pluripotent stem cell (iPSC)–derived microglia confirmed that dexamethasone directly suppresses inflammatory gene expression, indicating a conserved mechanism across species. This inflammatory suppression was recapitulated in both immortalized microglial (HMC3) and macrophage (THP1) cell lines. These findings suggest that localized dexamethasone delivered by CED reprograms the glioma immune microenvironment and achieves control of inflammation without the systemic adverse effects associated with standard systemic dexamethasone therapy. This clinically translatable strategy may improve symptom management and provide a platform for integrating local immunomodulation with future glioblastoma therapies.

Authors

Nathaniel W. Rolfe, Nicholas B. Dadario, Liang Lei, Anthony Tang, Misha Amini, Damian E. Teasley, Nkechime Ifediora, Peter Chabot, Nathan J. Winans, Nina Yoh, Julia Furnari, Corina Kotidis, Clara H. Stucke, Nivia M. Urena, Yanping Sun, Abby Brand, Ashwin Viswanathan, Pavan Upadhyayula, Michael G. Argenziano, Colin P. Sperring, Nadine Khoury, Nelson Humala, Shikun Wang, Justin Neira, Peter A. Sims, Brian J. Gill, Peter Canoll, Jeffrey N. Bruce