Search

The cancer immunotherapies involved in cGAS-STING pathway have been made great progress in recent years. STING agonists exhibit broad-spectrum anti-tumor effects with strong immune response. As a negative regulator of the cGAS-STING pathway, ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) can hydrolyze extracellular 2′, 3′-cGAMP and reduce extracellular 2′, 3′-cGAMP concentration. ENPP1 has been validated to play important roles in diabetes, cancers, and cardiovascular disease and now become a promising target for tumor immunotherapy. Several ENPP1 inhibitors under development have shown good anti-tumor effects alone or in combination with other agents in clinical and preclinical researches. In this review, the biological profiles of ENPP1 were described, and the structures and the structure–activity relationships (SAR) of the known ENPP1 inhibitors were summarized. This review also provided the prospects and challenges in the development of ENPP1 inhibitors. [Display omitted] • ENPP1 is a negative regulator of the cGAS-STING pathway. It became a promising target for tumor immunotherapy. • The biological profile of ENPP1 and its role in the occurrence of various diseases were described. • The design and structures of known inhibitors have been summarized in detail. • Provide new clues for the development of drugs targeting ENPP1 in tumor immunotherapy. [ABSTRACT FROM AUTHOR]