Carvedilol sensitizes chemotherapy by targeting STING to boost anti-tumor immunity.

The stimulator of interferon genes (STING)-mediated type I interferon (IFN) response is critical for mounting anti-tumor immunity and sensitizing chemotherapy by remodeling the tumor immune microenvironment. However, no clinically available drugs have been applied for STING activation. Based on high-throughput screening of small-molecule microarrays, we found that carvedilol, an adrenergic receptor blocker used to treat essential hypertension and symptomatic heart failure, is a STING activator. Mechanistically, carvedilol interacts with STING at threonine 263 and enhances its dimerization. Importantly, carvedilol enhances the therapeutic effect of etoposide in both the allografted tumor model and patient-derived tumor-like cell clusters (PTCs) by promoting etoposide-induced STING activation. Our findings identify carvedilol as a STING activator and provide a theoretical basis for combining carvedilol and etoposide in cancer therapy.