Single cell expression profiling of brain tumors in mice intracranially injected with 2x105 glioblastoma tumor cells isolated from NTv-a;hUBC-CreERT2;Adar1flox/flox mice and treated with tamoxifen to induce Adar1 deletion, or with vehicle control.

Glioblastomas are the most frequent and aggressive primary brain tumors. Current treatments invariably fail, a consequence of the pronounced heterogeneity and plasticity of glioblastoma cells, as well as the contribution of an immunosuppressive microenvironment that promotes tumor progression and resistance to therapy. Here, we exploited an innate immunity checkpoint, RNA sensing, to simultaneously target cancer cells and their supporting microenvironment. Using various immunocompetent mouse models of glioblastoma, we found that genetic deletion of Adar1, a key regulator of the RNA sensing pathway, resulted in significantly reduced tumor growth and prolonged survival. Mechanistically, these effects were mediated by two processes: cancer-cell intrinsic responses and reprogramming of the immune microenvironment that fostered a pro-inflammatory, anti-tumoral state via type I interferon signaling. These findings establish proof of concept for the therapeutic potential of targeting ADAR1 in glioblastoma, offering new strategies for the treatment of this aggressive disease. Comparative gene expression profiling of mouse glioblastoma tumor microenvironment upon deletion of Adar1.

胶质母细胞瘤（Glioblastomas）是最常见且恶性程度最高的原发性脑肿瘤。当前的治疗手段均告失败，这源于胶质母细胞瘤细胞显著的异质性与可塑性，以及促进肿瘤进展并诱发治疗抗性的免疫抑制性肿瘤微环境的参与。本研究利用先天免疫检查点——RNA感知通路——同时靶向肿瘤细胞及其支持性微环境。借助多种免疫健全的胶质母细胞瘤小鼠模型，我们发现作为RNA感知通路关键调控因子的RNA腺苷脱氨酶1（ADAR1）经遗传性敲除后，可显著抑制肿瘤生长并延长小鼠生存期。机制层面分析显示，上述效应由两类过程介导：肿瘤细胞内在的应答反应，以及通过I型干扰素信号通路重塑免疫微环境、形成促炎抗肿瘤状态的过程。本研究结果确立了靶向ADAR1治疗胶质母细胞瘤的概念验证，为这类恶性肿瘤的治疗提供了全新策略。本研究还对ADAR1敲除后的小鼠胶质母细胞瘤肿瘤微环境开展了比较基因表达谱分析。