Inhibition of <i>O</i>-GlcNAc transferase activates type I interferon-dependent antitumor immunity by bridging cGAS-STING pathway.

Abstract

The <i>O</i>-GlcNAc transferase (OGT) is an essential enzyme that mediates protein <i>O</i>-GlcNAcylation, a unique form of posttranslational modification of many nuclear and cytosolic proteins. Recent studies observed increased OGT and <i>O</i>-GlcNAcylation levels in a broad range of human cancer tissues compared to adjacent normal tissues, indicating a universal effect of OGT in promoting tumorigenesis. Here, we show that OGT is essential for tumor growth in immunocompetent mice by repressing the cyclic GMP-AMP synthase (cGAS)-dependent DNA sensing pathway. We found that deletion of OGT (<i>Ogt^-/-</i>) caused a marked reduction in tumor growth in both syngeneic mice tumor models and a genetic mice colorectal cancer (CRC) model induced by mutation of the <i>Apc</i> gene (<i>Apc^min</i>). Pharmacological inhibition or genetic deletion of OGT induced a robust genomic instability (GIN), leading to cGAS-dependent production of the type I interferon (IFN-I) and IFN-stimulated genes (ISGs). As a result, deletion of <i>Cgas</i> or <i>Sting</i> from <i>Ogt^-/-</i> cancer cells restored tumor growth, and this correlated with impaired CD8⁺ T-cell-mediated antitumor immunity. Mechanistically, we found that OGT-dependent cleavage of host cell factor C1 (HCF-1) is required for the avoidance of GIN and IFN-I production in tumors. In summary, our results identify OGT-mediated genomic stability and activate cGAS-STING pathway as an important tumor-cell-intrinsic mechanism to repress antitumor immunity.