Hijacking endogenous iron to amplify lysosomal-mitochondrial cascade damage for boosting anti-tumor immunotherapy

The cross-talk between lysosomes and mitochondria is crucial for keeping intracellular homeostasis and metabolic function, providing a promising approach for tumor therapy. Herein, we employed polyvinylpyrrolidone (PVP)-modified Cu-gallic acid (CuGA) complex nano-boosters for amplifying lysosomes-mitochondria cascaded damage, and thereby effectively inducing cuproptosis and pyroptosis of breast tumor cells to boost anti-tumor immunotherapy. The CuGA nano-boosters could hijack lysosomal iron to form a bimetallic catalyst Cu(Fe)GA in situ through ion-exchange reaction, and cause the release of Cu^+/2+ and metal ion dysregulation (i.e., Fe^2+/3+, Cu^+/2+, Ca²⁺) in tumor cells. The released Cu⁺ further led to metabolic disturbances of mitochondrial tricarboxylic acid (TCA) cycle (i.e., cuproptosis), and ultimately led to caspase-3/GSDME-dependent pyroptosis. In vivo results revealed that this lysosomal-mitochondrial cascade damage strategy not only induced tumor cell death, but also activated the immune response, thereby effectively suppressed tumor metastasis. This research provides a novel approach of triggering cascade damage to subcellular organelles for boosting tumor immunotherapy by disrupting metal ion intracellular homeostasis.