Tumor-Derived cGAMP Triggers a STING-Mediated Interferon Response in Non-tumor Cells to Activate the NK Cell Response

Abstract

<p id="P3">Detection of cytosolic DNA by the enzyme cGAS triggers the production of cGAMP, a second messenger that binds and activates the adaptor protein STING, which leads to interferon (IFN) production. Here we found that <i>in vivo</i>, natural killer (NK) cell killing of tumor cells, but not normal cells, depended on STING expression in non-tumor cells. Experiments using transplantable tumor models in STING and cGAS-deficient mice revealed that cGAS expression by tumor cells was critical for tumor rejection by NK cells. In contrast, cGAS expression by host cells was dispensable, suggesting that tumor-derived cGAMP is transferred to non-tumor cells where it activates STING. cGAMP administration triggered STING activation and interferon-β production in myeloid cells and B cells but not NK cells. Our results revealed that the anti-tumor response of NK cells critically depended on the cytosolic DNA sensing pathway similarly to its role in defense against pathogens, and identified tumor-derived cGAMP as a major determinant of tumor immunogenicity with implications for cancer immunotherapy. </p><p id="P4"> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/6234301e-cb9b-40fb-8293-a062ca8d6a49/PubMedCentral/image/nihms-1509345-f0001.jpg"/> </div> </p><p id="P5">Marcus et al. find that cGAMP produced by tumor cells triggers the activation of the STING pathway in immune cells within the tumor microenvironment, leading to interferon production by these cells, which in turn activates NK cell anti-tumor immunity. </p>