Cytomegalovirus Infection Is Associated with Accelerated Murine Glioblastoma Progression and Alterations in the Tumor Microenvironment

Glioblastoma (GBM) is a highly aggressive brain tumor with no effective treatments. It is characterized by rapid progression and marked heterogeneity, which contributes to therapeutic resistance. Human cytomegalovirus (hCMV), a highly prevalent β-herpesvirus, has been associated with GBM in numerous studies, and both antiviral drugs and hCMV-targeted immunotherapies have shown evidence of therapeutic activity in clinical trials. However, the mechanisms underlying this association remain poorly understood. To address this, we previously developed a murine model of GBM with murine CMV (mCMV) infection, which revealed accelerated tumor progression in infected mice. Here, we investigated whether tumor heterogeneity influences the effects of mCMV infection on intracranial tumor growth across four murine GBM models (GL261, CT-2A, M005 and Mut3). Tumor progression was monitored longitudinally by MRI and evaluated by survival analysis, histopathology and characterization of the tumor microenvironment. Systemic mCMV infection was associated with accelerated GBM progression across all models, characterized by increased tumor growth and significantly reduced survival. Enhanced tumor progression was accompanied by increased vascularization, elevated myeloid cell activation and intratumoral viral activity in a subset of tumors. Mass cytometry (CyTOF) revealed remodeling of the tumor immune landscape, including a marked increase in intratumoral virus-specific CD8+ T cells, highlighting a potential avenue for therapeutic targeting. Together, these findings indicate that CMV is associated with accelerated GBM progression across genetically distinct murine models, accompanied by remodeling of the tumor microenvironment, including increased vascularization and altered immune infiltration.