Silencing PCSK9 reshapes the spatiotemporal activation of STING for safe and effective cancer immunotherapy.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a central regulator of innate immunity and a promising target for cancer immunotherapy. However, the clinical translation of STING agonists is limited by suboptimal response rates and dose-limiting toxicities, particularly in the liver. These challenges highlight the presence of endogenous inhibitors of STING signaling and underscore the need for strategies that enable tissue-specific modulation of STING activity. Here, we identify proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of cholesterol metabolism, as a negative modulator of STING activation. Mechanistically, PCSK9 competes with STING for binding to a shared cargo receptor, which is critical for STING trafficking. PCSK9 deficiency markedly enhances the immunostimulatory effects of STING agonists. Capitalizing on the elevated expression of PCSK9 in the liver relative to tumors, we develop a formulation that delivers a low-dose STING agonist alongside PCSK9-targeting siRNA, thereby achieving tumor-selective STING activation while minimizing hepatotoxicity. These findings reveal an unanticipated role for PCSK9 in innate immune regulation and establish a therapeutic approach to enhance the safety and efficacy of STING-based immunotherapies, with broader implications for other STING-associated modalities, including radiotherapy and chemotherapy.