Cancer cell-extrinsic STING shapes immune-active microenvironment and predicts clinical outcome in gastric cancer

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.

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.

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.

Cancer cell-extrinsic STING facilitates the remodeling of immune-active tumor microenvironment and acts as an independent prognostic factor in gastric cancer.