ETD

• GABAergic signaling
• Glioblastoma
• immunotherapy
• murine model

Gliomas are highly aggressive brain tumors characterized by profound alterations in neuronal network activity within the peritumoral microenvironment. In particular, parvalbumin (PV)-expressing GABAergic interneurons play a pivotal role in maintaining cortical excitatory–inhibitory balance, and their dysfunction contributes to glioma-associated symptoms. This study investigated how chemogenetic modulation of PV-interneurons and pharmacological enhancement of GABA signaling affect tumor growth, cortical function, and survival in murine models. Selective PV-interneuron inactivation worsened symptoms and epileptiform activity without changing tumor volume or survival. Conversely, chronic PV-interneuron activation effectively reduced tumor proliferation and mass, while simultaneously preserving motor performance, network stability, and partially maintaining visual function. Similarly, Baclofen, a GABAB agonist, modestly decreased tumor volume and motor decline in GL261 tumors but not in the more aggressive CT-2A model, likely acting indirectly via the microenvironment. Notably, the combination of Baclofen with anti–PD-L1 immunotherapy produced a strong synergistic effect, leading to complete tumor eradication in 66% of mice and significantly extending survival. These findings suggest that enhancing peritumoral GABAergic inhibition can both stabilize cortical networks and improve the efficacy of immunotherapy in glioma.