Repurposing Eszopiclone A Non-Benzodiazepine GABA-A Modulator Synergizing with PD-1/PD-L1 Immunotherapy to Reprogram the Glioma Microenvironment – A Perspective

Background . Gliomas especially glioblastoma multiforme (GBM) are among the most aggressive primary brain tumors, characterized by rapid proliferation, metabolic plasticity, and a profoundly immunosuppressive tumor microenvironment (TME). Dysregulation of chloride homeostasis, glutamatergic excitotoxicity, and aberrant GABAergic signaling have recently emerged as mechanistic contributors to glioma progression and immune evasion. Purpose of the Study : to propose eszopiclone, a non-benzodiazepine GABA-A receptor modulator, as a repurposed adjunct capable of reprogramming glioma metabolism and enhancing responsiveness to PD-1/PD-L1 immunotherapy. Material and Methods. A narrative perspective review was conducted based on literature retrieved from PubMed, Scopus, Web of Science, and Science Direct. A total of 312 sources were screened; 154 articles published between 2005 and 2024 were selected for detailed analysis based on relevance to GABAergic signaling, glioma metabolism, macrophage polarization, chloride channel regulation, and immune checkpoint interactions. Results. Eszopiclone-mediated GABA-A activation restores chloride influx and suppresses depolarization-driven Ca²+/NFAT and PI3K/AKT/mTOR signaling, resulting in G1/S arrest and enhanced apoptotic susceptibility. Within the TME, GABA-A signaling reduces NF-κB and STAT3 phosphorylation and shifts microglia/glioma-associated macrophages from protumoral M2 (CD206+/IL-10+) to antitumoral M1 (iNOS+/IFN-γ+) polarization, facilitating improved antigen presentation and T-cell infiltration. Evidence from GABAergic models in melanoma and breast cancer suggests that modulation of this axis may downregulate PD-L1 expression and potentiate responsiveness to PD-1/PD-L1 inhibitors, supporting a mechanistic rationale for synergy in glioma. Conclusion . Repurposing eszopiclone introduces a novel neuroimmuno-oncologic therapeutic concept bridging neuropharmacology and checkpoint immunotherapy. Owing to its blood-brain-barrier penetration, clinical safety, and receptor selectivity, eszopiclone represents a feasible candidate for combination strategies with PD-1/PD-L1 blockade. Further preclinical models, retrospective analyses, and early-phase trials are warranted to validate its immunomodulatory potential and define its translational relevance in glioma therapy.