Glioblastoma (GBM) is an aggressive and immunosuppressed brain tumor with few therapeutic options. The development of novel therapies requires a better understanding of the bi-directional communication between the tumor and the surrounding brain parenchyma. On one hand, soluble factors released by GBM cells alter the balance of inhibitory and excitatory neurotransmission, and disrupt neural circuits; on the other, recent findings suggest that environmental stimuli modulate brain microenvironment with effects on brain plasticity, tumor cell growth and innate immune cell activation. Here, we will use mouse models of GBM to examine glioma-induced plastic reorganizations in peritumoral areas. Importantly, we will modulate physiological synaptic activity via environmental, sensory and optogenetic stimulation and study its impact on tumor biology and progression and on microglial/myeloid cell activation. Altogether, this project will shed new light on the interactions among neurons, tumor cells, glial cells and infiltrating immune cells, leading to the identification of novel cellular and molecular therapeutic targets and to the validation of non-invasive glioma therapies.