2',3'-cGAMP sodium (Synonyms: 2'-3'-cyclic GMP-AMP sodium)

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.