Beyond tumour suppression: cGAS-STING pathway in urologic malignancies: Context-dependent duality and therapeutic implications.

BACKGROUND: The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon (IFN) genes (STING) pathway emerges as a dual-functional role in urologic malignancies, exhibiting context-dependent tumor-suppressive and pro-tumorigenic activities. When this pathway is activated in urologic tumors, IFN transcription and CD8+ T cell infiltration are triggered, which has an anticancer effect. However, this pathway facilitates the development of prostate cancer through the up-regulation of regulatory B cells. STING palmitoylation triggers immune escape in renal cell carcinoma, and the STING/SLC14A1 axis also mediates chemoresistance in bladder cancer. MAIN TOPICS COVERED: Based on these findings, we establish the first systematic comparison of tissue-specific STING regulation in urological malignancies, challenging the conventional tumor suppressor-centric view. This review also highlights several innovative strategies leveraging this duality during urologic cancers. The demand for the long-term safety and effectiveness of these targeted STING treatments has not been fully met. CONCLUSIONS: This study introduces a framework that harnesses the dual functions of the cGAS-STING pathway to strengthen immunotherapy approaches and improve clinical outcomes to bridge the pre-clinical-clinical gap. KEY POINTS: The context-dependent duality of cGAS-STING signalling in urologic tumours is revealed. Targeting the STING pathway, in combination with immunotherapies and gene therapies, enhances the anti-tumour response. Sex hormone differences in urological malignancies are correlated with the cGAS-STING pathway.