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

ABSTRACT: 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 defici

SUBMITTER: Sun P 

PROVIDER: S-EPMC12749358 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature