ENPP1 is the dominant hydrolase of extracellular cGAMP in the STING pathway but has rich cGAMP-STING-independent pathophysiology. Mounting evidence shows that ENPP1 has pro-cancer roles with unclear mechanisms. Using ENPP1 genetic knockout in a murine breast cancer model, we showed that ENPP1 dampens immune infiltration and activation. In parallel, specific depletion of extracellular cGAMP from the tumor microenvironment yields a similar immune signature. Furthermore, using a genetic knock-in mouse harboring an ENPP1 mutation specifically defective towards cGAMP hydrolysis, we demonstrated that ENPP1’s cGAMP degradation activity alone is sufficient to facilitate tumor progression. ENPP1 on both cancer and normal tissues contributes to its innate immune checkpoint activity and should be blocked to turn cold tumors hot. Finally, ENPP1 activity levels vary in mouse tissues and human donors and the common K173Q allele harbors markedly increased activity, a discovery with profound implications in patient selection for ENPP1-based cancer immunotherapy.

ENPP1 is an innate immune checkpoint by degrading extracellular cGAMP

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.