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 and metal ion dysregulation (i.e., Fe, Cu, Ca) 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.