AbstractGlioblastoma (GBM) is the most aggressive primary brain tumor with a dismal prognosis, and effective treatments, especially for recurrent disease, are lacking. Standard therapies offer limited benefit, potentially due to GBM's unique immunosuppressive tumor microenvironment (TME). This study investigates the therapeutic potential and mechanisms of Ad-REIC, a non-replicating adenoviral vector expressing the tumor suppressor gene REIC/Dkk-3, developed at Okayama University. We compared a first-generation vector (Ad-CAG-REIC) with a second-generation vector featuring enhanced enhancers (Ad-SGE-REIC) using in vitro human and mouse GBM cell lines and in vivo mouse models. Ad-SGE-REIC demonstrated superior REIC/Dkk-3 expression and significantly stronger tumor-killing effects in vitro. In GBM-bearing mice, Ad-SGE-REIC treatment resulted in significantly prolonged survival compared to Ad-CAG-REIC and controls, with some mice achieving long-term survival. Mechanistic analysis revealed that Ad-REIC induces direct tumor cell apoptosis and endoplasmic reticulum (ER) stress, leading to immunogenic cell death. This effect was potentiated by combination with bevacizumab. Furthermore, Ad-REIC remodeled the TME by significantly increasing the infiltration of CD11c+ dendritic cells and CD8+ lymphocytes, particularly with Ad-SGE-REIC. Transcriptomic analysis of treated tumors showed upregulation of immune-related pathways such as NOTCH and TNFα/NF-κβ signaling. These findings suggest Ad-REIC exerts anti-GBM effects through both direct cytotoxicity and indirect activation of anti-tumor immunity via TME modulation. The enhanced Ad-SGE-REIC vector shows promise as a novel immunotherapy for GBM, potentially synergizing with existing therapies. Ongoing research using samples from a Phase I/IIa clinical trial aims to validate these findings in humans, identify biomarkers for treatment response and resistance, and facilitate clinical translation.岡山大学学術研究院医歯薬学域脳神経外科・研究准教授Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences大谷 理浩Yoshihiro Otani― 149 ―腫瘍微小環境の再構築による，膠芽腫に対する新規免疫療法の開発Development of novel immunotherapy for glioblastoma by remodeling the tumor microenvironment
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