Molecular map of cGAS-STING pathway-related genes in bladder cancer: the perspective toward immune microenvironment and prognosis

Background: The cGAS-STING pathway emerges as a pivotal innate immune pathway with the potential to profoundly influence all facets of tumor initiation and progression. The prognostic significance and immunological role of cGAS-STING pathway-related genes (CRGs) in individuals diagnosed with bladder cancer (BLCA) have not yet been fully elucidated. Methods: Performed unsupervised cluster analysis to identify distinct clusters. Utilizing LASSO and multivariate Cox regression analysis to construct a prognostic risk model. The IMvigor210, GSE13507 and GSE78220 cohorts were utilized to explore the potential value of risk score in immune therapy response and survival prediction. Results: A risk model was developed utilizing four CRGs in order to forecast the overall survival (OS) of BLCA patients. The risk score to be a standalone risk factor, which was further corroborated by the external validation set obtained from the GEO database (GSE13507). We established an integrated nomogram that combined risk scoring and clinical information, exhibiting commendable clinical practicality in predicting the overall survival period of BLCA patients. It is noteworthy that risk score could differentiate tumor microenvironments among different risk groups and individuals who were more responsive to immunotherapy in IMvigor210 and GSE13507 cohorts. In vitro experiments, we noted an up-regulation of IRF3 and IKBKB upon the activation of the cGAS-STING pathway. Conversely, the activation of the cGAS-STING pathway resulted in a down-regulation of POLR3G and CTNNB1. Conclusions: CRG risk model shows promise as a potential stratification approach for bladder cancer patients.