Cancer Cell-Extrinsic STING Shapes Immune-Active Microenvironment and Predicts Clinical Outcome in Gastric Cancer

PURPOSE:The activation of cGAS-STING pathway can be triggered by cytosolic double-stranded DNA (dsDNA) in tumor and non-tumor compartments. We aim to assess the constitutive expression of dsDNA-cGAS-STING axis in different cellular contexts and compare their relative contribution to clinical outcomes. METHODS:A cohort of 154 cases of patients with newly diagnosed gastric cancer were enrolled in this study to evaluate the histo-score of cytosolic dsDNA, cGAS, and STING via immunohistochemistry as well as the types and densities of tumor-infiltrating immune cells. Kaplan-Meier method, multivariable regression, and receiver operating characteristic curve were implemented to analyze the prognostic efficacy of dsDNA-cGAS-STING axis in distinct compartments. RESULTS:The supra-normal concentration of cytosolic dsDNA correlated with the constitutive expression of cGAS-STING pathway in tumor compartments. In contrast to the lack of STING within cancer cells, the higher STING expression in non-tumor compartments indicated a transcellular cGAS-STING activation. Cancer cell-extrinsic STING was supported to potentiate nucleic acid immunity by sensing tumor-derived dsDNA fragments. Compartmental analyses also confirmed that the level of STING expressed in non-tumor cells was associated with the infiltration of protective immune cells, leading to the prolonged overall survival. Multivariate analysis further identified the independent prognostic value of cancer cell-extrinsic STING and its predictive accuracy could be significantly improved in combination with the immune cell infiltration. CONCLUSIONS:Cancer cell-extrinsic STING facilitates the remodeling of immune-active tumor microenvironment and acts as an independent prognostic factor in gastric cancer.