2′3′-cGAMP sodium is a second messenger that binds and activates the adaptor protein stimulator of interferon (STING), which triggers the innate immune response [1]. As a STING agonist, the small molecule 2′3′-cGAMP sodium plays pivotal roles in antiviral defense and has adjuvant applications, and anti-tumor effects. 2′3′-cGAMP sodium and its analogs are thus putative targets for immunotherapy and are currently being tested in clinical trials to treat solid tumors.
2′3′-cGAMP sodium is capable of enhancing the proinflammatory activation of cultured Wild-type (WT) macrophages. Unlike in macrophages (BMDM), 2′3′-cGAMP sodium treatment displayed anti-inflammatory effects in both WT primary mouse hepatocytes and differentiated 3T3-L1 adipocytes. Specifically, LPS-induced JNK p46 and NF-κB p65 phosphorylation states and IL-1β and TNFα mRNAs in 2′3′-cGAMP sodium -treated WT primary mouse hepatocytes were significantly lower than their respective levels in control-treated hepatocytes. In 3T3-L1 adipocytes, the anti-inflammatory effect of 2′3′-cGAMP sodium was even more pronounced. In particular, LPS-induced JNK p46 phosphorylation states in 2′3′-cGAMP sodium -treated adipocytes were markedly lower than in control-treated adipocytes, and were comparable with JNK p46 phosphorylation states in 2′3′-cGAMP sodium -treated adipocytes in the absence of LPS induction [2].
2′3′-cGAMP sodium and CpG-C co-administration adjuvants had a synergistic effect to establish a shift towards the Th1(T helper type 1) immune response, and leading to reduced tumor growth. This vaccine formulation could be a promising therapeutic candidate vaccine for HPV 16 established infections and HPV-associated tumors [3]. 2′3′-cGAMP sodium led to a marked CD8 T cell increase in tumors; combined treatment further increased the percentage of CD8 T cells [4].
References:
[1]. Su M, Zheng J, Gan L, Zhao Y, Fu Y, Chen Q. Second Messenger 2’3’-Cyclic GMP-AMP (2’3’-cGAMP):Synthesis, Transmission, and Degradation. Biochem Pharmacol (2022) 198:114934. doi: 10.1016/j.bcp.2022.114934
[2]. X. Guo, C. Shu, H. Li, et al. Cyclic GMP-AMP ameliorates diet-induced metabolic dysregulation and regulates proinflammatory responses distinctly from STING activation Sci Rep, 7 (2017), p. 6355
[3]. Dorostkar, F.; Arashkia, A.; Roohvand, F. et al. Co-administration of 2’3’-cGAMP STING activator and CpG-C adjuvants with a mutated form of HPV 16 E7 protein leads to tumor growth inhibition in the mouse model. Infect. Agents Cancer 2021, 16, 7.
[4]. Lai J, Fu Y, Tian S, et al. Zebularine elevates STING expression and enhances cGAMP cancer immunotherapy in mice. 2021. Mol Ther 29: 1758–1771.
2'3'-cGAMP 钠是第二信使,可结合并激活干扰素 (STING) 的衔接蛋白刺激因子,从而触发先天免疫反应[1]。作为 STING 激动剂,小分子 2'3'-cGAMP 钠在抗病毒防御中起着关键作用,并具有辅助应用和抗肿瘤作用。 2'3'-cGAMP 钠及其类似物因此被推定为免疫治疗的靶标,目前正在临床试验中测试以治疗实体瘤。
2'3'-cGAMP 钠能够增强培养的野生型 (WT) 巨噬细胞的促炎激活。与巨噬细胞 (BMDM) 不同,2'3'-cGAMP 钠处理在 WT 原代小鼠肝细胞和分化的 3T3-L1 脂肪细胞中均显示出抗炎作用。具体而言,LPS 诱导的 JNK p46 和 NF-κB p65 磷酸化状态以及 2'3'-cGAMP 钠处理的 WT 原代小鼠肝细胞中的 IL-1β 和 TNFα mRNA 显着低于其在对照处理的肝细胞中各自的水平。在 3T3-L1 脂肪细胞中,2'3'-cGAMP 钠的抗炎作用更为明显。特别是,在 2'3'-cGAMP 钠处理的脂肪细胞中,LPS 诱导的 JNK p46 磷酸化状态明显低于对照处理的脂肪细胞,并且与 2'3'-cGAMP 钠处理的脂肪细胞中的 JNK p46 磷酸化状态相当在没有 LPS 诱导的情况下 [2]。
2'3'-cGAMP 钠和 CpG-C 联合给药佐剂具有协同作用,可建立向 Th1（T 辅助细胞 1 型）免疫反应的转变,并导致肿瘤生长减少。这种疫苗制剂可能是一种很有前途的治疗性候选疫苗,可用于治疗 HPV 16 感染和 HPV 相关肿瘤[3]。 2'3'-cGAMP 钠导致肿瘤中 CD8 T 细胞显着增加；联合治疗进一步提高了CD8 T细胞的比例[4]。