2’-3’-cGAMP (cGAMP) is a potent immunotransmitter essential to mounting an effective immune response against cancer. cGAMP is synthesized upon appearance of dsDNA in the cytosol of cancerous cells. Once produced, cGAMP activates the Stimulator of Interferon Genes (STING) pathway, leading to the production of cytokines that drive tumor regression. However, cGAMP is frequently hydrolyzed, resulting in a reduced immune response against cancer. This negative regulation of cGAMP represents a key innate immune checkpoint that can harnessed to improve outcomes against cancer. We previously characterized ENPP1 as a cGAMP hydrolase. Potent inhibitors against ENPP1 have been developed and are showing great promise in preclinical data, delaying tumor growth and improving cancer survival rates in mice. However, we discovered that ENPP1 accounts for only half of the cGAMP hydrolysis activity in most tissues in mice. Through column-based fractionation of ENPP1<sup>-/-</sup> mouse organs and mass spectrometry proteomics analysis, we identified a second cGAMP hydrolase. Subsequent biochemical characterization identified dual-function inhibitors that act potently against both known cGAMP hydrolases. Our discoveries establish the foundation for the development of potential drugs for anti-cancer immunotherapies.

Identification of a novel cGAMP hydrolase as a cancer immune checkpoint

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.