Constant cGAS activation blunts STING signaling in DU145 prostate cancer cell line.

The cGAS-STING pathway is an innate immune pathway that senses microbial and host-derived double-stranded DNA in the cytosol, and triggers type I interferon responses and proinflammatory cytokine production. Recently, activation of the cGAS-STING pathway in tumors is reported to enhance anti-tumor effects, while it is often inactivated in tumors. Therefore, to develop strategies to activate STING in tumors has become imperative in cancer therapy. Here we report that the cGAS-STING signaling is inactivated in DU145 prostate cancer cell line and find that the inactivation mechanism is distinct from the previously reported mechanisms such as DNA methylation. Treatment of DU145 cells with a lysosomal inhibitor Baf-A1 increased a STING protein level. Knockdown of VPS4, the essential factor in lysosomal microautophagy, suppresses STING degradation. Most importantly, knockdown of cGAS, the enzyme responsible for the production of the endogenous STING ligand cGAMP, fully restores a STING protein level and a response to a synthetic membrane-permeable STING agonist MSA-2. Thus, these results suggest that the constant cGAS activation causes the lysosomal degradation of STING and underlies the unresponsiveness of the STING signaling in DU145 cells. Our results may lead to new strategies to enhance STING-targeted cancer immunotherapy.