Spatiotemporally Controlled Lysosomal Membrane Permeabilization Amplifies STING‐Driven Antitumor Immunity in Prostate Cancer

Abstract

ABSTRACT Prostate cancer (PCa) remains a major clinical challenge due to therapeutic resistance and immunologically cold tumor microenvironment. Lysosomal membrane permeabilization (LMP)–induced lysosome‐dependent cell death offers an alternative route to eliminate resistant tumor cells and initiate immunogenic cell death, yet its efficacy is often limited by insufficient spatiotemporal control and immune activation. Here, we report a spatiotemporally programmable supramolecular nanoplatform (Cu‐P‐MSA) that integrates lysosome‐targeted sonodynamic therapy with tumor‐confined innate immune activation for PCa treatment. Cu‐P‐MSA is a modular self‐assembling peptide incorporating a PSMA‐targeting ligand, morpholine moiety, and cathepsin B–cleavable linker, enabling tumor‐selective uptake and in situ formation of fibrous sonosensitizer depots within lysosomes. Upon ultrasound irradiation, a glutathione‐responsive open‐shell sonosensitizer induces controlled LMP, simultaneously activating ferroptosis and pyroptosis and promoting immunogenic cell death. Meanwhile, tumor‐specific release of a STING agonist MSA‐2 elicits robust type I interferon responses, driving dendritic cell maturation and cytotoxic T‐cell infiltration. This coordinated lysosomal disruption–immune amplification strategy effectively reprograms the tumor immune microenvironment and suppresses both primary and distant tumors, with inhibition rates reaching 84.3% and 77.5%, respectively. Overall, this work establishes a spatiotemporally controlled supramolecular approach that integrates lysosomal disruption with innate immune activation to overcome therapeutic resistance and immunosuppression in PCa.