Modulation of peritumoral inhibitory circuits and GABAergic signaling in Glioblastoma progression and therapeutic response

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.