Zhou Shurong, Su Ting, Cheng Furong, Cole Janet, Liu Xiang, Zhang Bei, Alam Shaheer, Liu Jinze, Zhu Guizhi
Department of Pharmaceutical Sciences, College of Pharmacy; Biointerfaces Institute. University of Michigan. Ann Arbor, MI 48109, USA.
Department of Pharmaceutics and Center for Pharmaceutical Engineering and Sciences, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA.
bioRxiv. 2023 Jul 13:2023.07.13.548237. doi: 10.1101/2023.07.13.548237.
Current cancer immunotherapy (e.g., immune checkpoint blockade (ICB)) has only benefited a small subset of patients. Cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) activation holds the potential to improve cancer immunotherapy by eliciting type-I interferon (IFN-I) responses in cancer cells and myeloid cells. Yet, current approaches to this end, mostly by targeting STING, have marginal clinical therapeutic efficacy. Here, we report a cGAS-specific agonistic oligonucleotide, Svg3, as a novel approach to cGAS-STING activation for versatile cancer immunotherapy. Featured with a hairpin structure with consecutive guanosines flanking the stem, Svg3 binds to cGAS and enhances cGAS-Svg3 phase separation to form liquid-like droplets. This results in cGAS activation by Svg3 for robust and dose-dependent IFN-I responses, which outperforms several state-of-the-art STING agonists in murine and human immune cells, and human tumor tissues. Nanocarriers efficiently delivers Svg3 to tissues, cells, and cytosol where cGAS is located. Svg3 reduces tumor immunosuppression and potentiates ICB therapeutic efficacy of multiple syngeneic tumors, in wildtype but neither nor goldenticket mice. Further, as an immunostimulant adjuvant, Svg3 enhances the immunogenicity of peptide antigens to elicit potent T cell responses for robust ICB combination immunotherapy of tumors. Overall, cGAS-agonistic Svg3 is promising for versatile cancer combination immunotherapy.
目前的癌症免疫疗法（如免疫检查点阻断疗法（ICB））仅使一小部分患者受益。环磷酸鸟苷-腺苷酸合成酶-干扰素基因刺激因子（cGAS-STING）激活具有通过在癌细胞和髓样细胞中引发I型干扰素（IFN-I）反应来改善癌症免疫疗法的潜力。然而，目前为此目的的方法主要是靶向STING，临床治疗效果有限。在此，我们报告一种cGAS特异性激动寡核苷酸Svg3，作为一种用于通用癌症免疫疗法的cGAS-STING激活新方法。Svg3具有发夹结构，其茎两侧有连续的鸟苷，它与cGAS结合并增强cGAS-Svg3相分离以形成液滴样小滴。这导致Svg3激活cGAS以产生强大且剂量依赖性的IFN-I反应，在小鼠和人类免疫细胞以及人类肿瘤组织中，其表现优于几种最先进的STING激动剂。纳米载体可有效地将Svg3递送至cGAS所在的组织、细胞和细胞质中。在野生型小鼠而非 或金票小鼠中，Svg3可减轻肿瘤免疫抑制并增强多种同基因肿瘤的ICB治疗效果。此外，作为一种免疫刺激佐剂，Svg3增强肽抗原的免疫原性，以引发有效的T细胞反应，用于肿瘤的强大ICB联合免疫疗法。总体而言，cGAS激动剂Svg3在通用癌症联合免疫疗法方面具有前景。
