MSH6 regulates cGAS activity in antiviral and antitumor signaling pathways by governing its cytosolic/nuclear distribution

While the cytosolic localization of cGAS is critical for cells to initiate immune responses and protect cells from viral infections, the activity of cGAS in the nucleus is inhibited to prevent autoimmune responses triggered by self-DNA. Therefore, the dynamically regulated distribution of cGAS in the cytosol and nucleus ensures its precise role in maintaining immune homeostasis. However, the molecular mechanism governing this spatial distribution of cGAS remains unclear. Here, we identify MSH6 as a regulator promoting cGAS nuclear localization by enhancing its association with importin-α proteins, consequently reducing cGAS condensation and activity. We further show that MSH6 attenuates antitumor immunity and that its deficiency in tumor cells leads to an effective tumor eradication by heat-inactivated modified vaccinia virus Ankara. Collectively, our results not only provide insights into understanding how cGAS activity is regulated but also suggest a therapeutic potential for treating MSH6-mutated tumors through the cGAS-mediated signaling pathway.