Sonodynamic/Mechano‐Induced cGAMP Biosynthesis Enables In Situ STING Activation for Enhanced Cancer Immunotherapy

ABSTRACT Activation of the stimulator of interferon genes (STING) signaling pathway holds great promise for enhancing antitumor immunity. However, its clinical use has been hindered due to the inefficient cytosolic delivery of STING agonists. We herein report an alternative approach that leverages acoustic waves to boost the biosynthesis of endogenous agonist cGAMP (cyclic GMP‐AMP) for in situ STING activation in tumor cytoplasm. To transduce ultrasound for bio‐intervention, a sono‐responsive protein conjugate named SIGMA is constructed by anchoring a sonosensitizer to a tumor‐specific nuclear targeting fusion protein. Intravenously injected SIGMA preferentially targets tumor cell nuclei and promotes DNA damage and cGAS (cyclic GMP‐AMP synthase) production upon ultrasound stimulation. Acoustic waves concurrently disrupt nuclear integrity, enabling substantial export of both triggers into the cytosol to initiate cGAMP biosynthesis. The resulting cGAMP not only directly activates STING in tumor cells but also diffuses to proximal immune cells, inducing robust anti‐tumor immunity that significantly inhibits tumor growth and prolongs survival, as well as establishing long‐lasting immune memory that suppresses tumor rechallenge. This study thus highlights an efficient and translatable strategy that harnesses acoustic regulation of natural biosynthetic routes to improve cancer immunotherapy.