胶质母细胞瘤 (GBM) 是一种侵袭性脑肿瘤，中位生存期为 15 个月，治疗选择有限。使用检查点抑制剂的免疫疗法在对抗 GBM 方面显示出极低的疗效，并且大型临床试验也失败了。需要新的免疫治疗方法和对 GBM 免疫监视的更深入了解，才能推进这种破坏性疾病的治疗方案。在这项研究中，我们使用了两种 GBM 临床前模型：原位递送 GBM 干细胞或利用腺相关病毒 CRISPR 介导的肿瘤发生，分别建立免疫充分的和非炎症的肿瘤。肿瘤发生后，先天免疫系统通过药理学激动剂的长期 STING 激活而被激活，从而减少肿瘤进展并延长生存期。在肿瘤中检测到细胞毒性 T 细胞的募集和激活，并观察到 ​​T 细胞对癌细胞的特异性。有趣的是，通过激酶组阵列和 VEGF 表达测量，延长的 STING 激活改变了肿瘤脉管系统，诱导缺氧和 VEGFR 激活。与抗 PD1 的联合治疗没有提供协同效应，表明单独激活 STING 就足以激活免疫监视并通过血管破坏阻碍肿瘤的发展。这些结果指导未来的研究，以完善先天免疫激活作为 GBM 的治疗方法，与抗 VEGF 相结合，阻止肿瘤进展并诱导针对肿瘤的免疫反应。版权所有 © 2023。由 Elsevier B.V 出版。

Glioblastoma (GBM) is an aggressive brain tumor with a median survival of 15 months and has limited treatment options. Immunotherapy with checkpoint inhibitors has shown minimal efficacy in combating GBM, and large clinical trials have failed. New immunotherapy approaches and a deeper understanding of immune surveillance of GBM are needed to advance treatment options for this devastating disease. In this study, we used two preclinical models of GBM: orthotopically delivering either GBM stem cells or employing CRISPR-mediated tumorigenesis by adeno-associated virus, to establish immunologically proficient and non-inflamed tumors, respectively. After tumor development, the innate immune system was activated through long-term STING activation by a pharmacological agonist, which reduced tumor progression and prolonged survival. Recruitment and activation of cytotoxic T-cells were detected in the tumors, and T-cell specificity towards the cancer cells was observed. Interestingly, prolonged STING activation altered the tumor vasculature, inducing hypoxia and activation of VEGFR, as measured by a kinome array and VEGF expression. Combination treatment with anti-PD1 did not provide a synergistic effect, indicating that STING activation alone is sufficient to activate immune surveillance and hinder tumor development through vascular disruption. These results guide future studies to refine innate immune activation as a treatment approach for GBM, in combination with anti-VEGF to impede tumor progression and induce an immunological response against the tumor.Copyright © 2023. Published by Elsevier B.V.