Small molecule ectonucleotide pyrophosphatase/phosphodiesterase 1 inhibitors in cancer immunotherapy for harnessing innate immunity

Abstract

Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) was recently identified as a major hydrolase of an endogenous stimulator of interferon genes (STING) agonist, 2′,3′-cyclic guanosine monophosphate–adenosine monophosphate (cGAMP). ENPP1 is a promising therapeutic target in cancer immunotherapy, in which the inhibition of ENPP1 enhances anticancer immunity via STING-mediated innate immune activation. This review highlights the role of ENPP1 in innate immunity and the recent discovery of small molecule ENPP1 inhibitors as immunomodulators in cancer immunotherapy.