2',3'-cGAMP sodium (2'-3'-cyclic GMP-AMP sodium) is a second messenger in cellular innate immunity, catalyzed by cGAMP synthase (cGAS) under DNA binding conditions. It binds to STING to form a dimer, inducing the production and expression of interferon-β and other cytokines.

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]

At 7 days after tumor cell inoculation, the mice were treated with zebularine alone, 2’,3’-cGAMP sodium alone, or the combination of both. A final concentration of 2.5 mg/mL zebularine was added to drinking water for 10 days until the mice were collected for conducting further experiments. A total of 100 μL of 10μg 2’,3’-cGAMP sodium in PBS at the indicated concentrations was injected into the site next to tumor. 2’,3’-cGAMP sodium treatment was repeated three times with 4-day intervals. This study unveils the role of zebularine in sensitizing the cGAS-STING pathway to promote anti-tumor immunity.[4]