Microbiota-derived secondary bile acids promote STING activation and antitumor activity

Abstract Microbiota metabolism generates diverse bile acids that are associated with health and disease, but the molecular targets and mechanisms of action for these metabolites have not been fully elucidated. Using bile acid photoaffinity probes and chemoproteomics, we found many protein targets of microbiota-derived secondary bile acids in mammalian cells. Of note, we discovered deoxycholic acid (DCA) binds the transmembrane domain of stimulator of interferon genes (STING), promotes its oligomerization and agonist stimulation of type I interferon signaling ex vivo and antitumor immunity in vivo. Moreover, oral administration of DCA-producing microbiota species enhanced STING agonist antitumor immunity in vivo. This reverse chemical microbiology approach revealed an unpredicted mechanism of action for DCA on STING regulation and suggests specific secondary bile acids and their associated microbiota species may impact the efficacy of STING-targeted therapeutics. Competing Interest Statement LLL has filed and issued patents associated with synthetic STING agonists. All other authors declare that they have no competing interests. Footnotes Figure 3-5 revised: Validation of the STING transmembrane mutant activity in STING-KO THP-1 cells; New antibiotic and vancomycin controls, quantitative fecal/serum DCA measurements, and expanded data showing that Clostridium scindens (but not C. sporogenes) enhances diABZI-induced IFN-b and antitumor responses.