Cholesterol regulator suppresses innate immunity in cancer immunotherapy

Cholesterol levels are negatively correlated with the innate immunity, which plays a crucial role in fighting cancer and pathogens. However, much is still unknown about the underlying mechanism of how cholesterol levels regulate key innate immune pathways, such as the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. Here we report that proprotein convertase subtilisin/kexin type 9 (PCSK9), currently known for its role in controlling systemic cholesterol, competes with STING for binding to a cargo receptor that mediates STING trafficking. Consequently, PCSK9 deficiency efficiently amplifies STING activation. Importantly, systemic administration of a nanoparticle containing PCSK9 siRNA and a STING agonist can efficiently activate STING and thus provide sufficient antitumor immunity to regress established tumors. Our study both sheds light on the importance of PCSK9 in regulating STING activation and provides an efficient strategy for activating antitumor immunity, with broad and immediate applications for cancer immunotherapy.