Enpp3, also known as ectonucleotide pyrophosphatase/phosphodiesterase 3, is an extracellular membrane protein. It belongs to the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family, which is involved in nucleotide and phospholipid signaling, among other biological processes [2]. Enpp3 has been identified as a major cGAMP hydrolase, regulating cGAMP levels to dampen anti-cancer immunity, and it also plays a role in innate immune cell-cell communication through extracellular cGAMP-STING signaling [1,3].

Selectively abolishing Enpp3's cGAMP hydrolysis activity in certain mouse models leads to diminished cancer growth and metastasis of some tumor types in a stimulator of interferon genes (STING)-dependent manner, indicating its role as an innate immune checkpoint [1,3]. In ENPP1-deficient mice, Enpp3 accounts for all cGAMP hydrolysis activity, highlighting its significance in this context [1,3].

In conclusion, Enpp3 is a crucial regulator in innate immune signaling, especially in controlling cGAMP-mediated anti-cancer immunity. Studies using gene-knockout mouse models have revealed its potential as a target for cancer immunotherapy, emphasizing the importance of this gene in cancer-related disease areas [1,3].

References:

1. Mardjuki, Rachel, Wang, Songnan, Carozza, Jacqueline, Goodarzi, Hani, Li, Lingyin. 2024. Identification of the extracellular membrane protein ENPP3 as a major cGAMP hydrolase and innate immune checkpoint. In Cell reports, 43, 114209. doi:10.1016/j.celrep.2024.114209. https://pubmed.ncbi.nlm.nih.gov/38749434/

2. Borza, Razvan, Salgado-Polo, Fernando, Moolenaar, Wouter H, Perrakis, Anastassis. 2021. Structure and function of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family: Tidying up diversity. In The Journal of biological chemistry, 298, 101526. doi:10.1016/j.jbc.2021.101526. https://pubmed.ncbi.nlm.nih.gov/34958798/

3. Mardjuki, Rachel, Wang, Songnan, Carozza, Jacqueline A, Lyu, Xuchao, Li, Lingyin. 2024. Identification of extracellular membrane protein ENPP3 as a major cGAMP hydrolase, cementing cGAMP's role as an immunotransmitter. In bioRxiv : the preprint server for biology, , . doi:10.1101/2024.01.12.575449. https://pubmed.ncbi.nlm.nih.gov/38260585/