Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1), also known as Plasma-Cell Membrane Glycoprotein (PC-1) and CD203a, is a member the ecto-enzyme ENPP family that includes seven members (ENPP1-ENPP7)¹.

ENPP1 is involved in purinergic signaling as it catalyzes the hydrolysis of ATP or GTP to AMP or GMP, while generating inorganic pyrophosphates (PPi)^1,2. Inorganic pyrophosphates inhibit bone and cartilage mineralization, hence making ENPP1 a key regulator of bone and cartilage development and remodeling ^2,3. Indeed, several hereditary mineralization or calcification-related disorders, have been linked to loss-of-function mutations of ENPP1, such as  general arterial calcification of infancy (GACI) or Cole disease ³.

Recently, an intriguing new role of ENPP1 as a central regulator of immunity and tumor proliferation came to light. It was shown that ENPP1 is the critical enzyme that degrades the stimulator of interferon genes (STING) ligand, cyclic GMP–AMP (cGAMP)^4,5. cGAMP was first described as an intracellular second messenger, synthesized by the enzyme cyclic-GMP-AMP synthase (cGAS) in response to self and pathogenic double-stranded DNA in the cytosol. Intracellular signaling of cGAMP is carried through the STING pathway which then directs several antiviral and anticancer cellular response mechanisms ^4,5.

cGAMP can also be released to the extracellular space where it can be transported into cells by receptors like MERTK ⁶, P2X7 ⁶, SLC19A1 ⁷ and LRRC8A ⁸. ENPP1 is the only known ecto-enzyme that can inactivate extracellular cGAMP to GMP and AMP, and thus functions as an inhibitor of the anti-tumor response elicited by extracellular cGAMP ^4,9.