Enpp1, also known as ectonucleotide pyrophosphatase/phosphodiesterase 1, codes for a type 2 transmembrane glycoprotein. Its primary function is to hydrolyze extracellular ATP to generate pyrophosphate (PPi) and adenosine monophosphate, contributing to downstream purinergic signaling pathways. Pyrophosphate generated by Enpp1 is a key inhibitor of hydroxyapatite formation, thus playing a crucial role in regulating skeletal and soft tissue mineralization. It is also involved in the cGAMP-STING signaling pathway, which is important for the innate immune response [1,3,5].

Loss-of-function experiments in both cancer cells and normal tissues have shown that Enpp1 drives primary breast tumor growth and metastasis by dampening extracellular cGAMP-STING-mediated antitumoral immunity. Enpp1 loss-of-function slowed primary tumor growth and abolished metastasis. Selectively abolishing the cGAMP hydrolysis activity of Enpp1 phenocopied Enpp1 knockout in a STING-dependent manner. In addition, ENPP1 deficiency in humans causes a range of age-dependent symptoms including cardiovascular complications and high infant mortality, autosomal recessive hypophosphatemic rickets type 2 in children, and joint-related problems in adults [2,4].

In conclusion, Enpp1 is essential for regulating mineralization processes in the body, and its role in the cGAMP-STING signaling pathway significantly impacts the innate immune response. The use of Enpp1 knockout or conditional knockout mouse models and other loss-of-function experiments have revealed its crucial role in breast cancer progression and in the pathophysiology of ENPP1 deficiency-related diseases, providing valuable insights for developing therapeutic strategies for these conditions [1-6].