The Tripartite Cascade Strategy Amplifies Cellular Oxidative Stress to Disrupt Oxidation–Reduction Homeostasis for Tumor Immunogenic Cell Death

Immunogenic cell death (ICD) induced by intracellular oxidation–reduction homeostasis imbalance is a classic mechanism in cancer immunotherapy. Herein, we propose a tripartite strategy to amplify cellular oxidative stress based on a combination of peptidic nanoparticles (TPF NO /CCA NPs) of host–guest drug-loading, fibrillar transformation, and NO generation. Cinnamaldehyde (CA) was released from TPF NO /CCA NPs due to Schiff base bond breakage within the lysosome, promoting excessive ROS generation. The residual TPF NO /C NPs bind the mitochondria, where excessive ROS induces the host–guest disintegration of ferrocene/β-cyclodextrin. The β-sheet TPF NO peptide could further transform into a fibrillar network on the mitochondria surface, leading to a further surge of ROS. Concurrently, the TPF NO peptide would locally release NO gas by consuming intracellular glutathione. NO further reacts with ROS and yields ONOO –, exacerbating mitochondrial dysfunction. Through a synergistic cascade of ROS generation and glutathione consumption, TPF NO /CCA NPs efficiently amplify oxidative stress, inducing potent immunogenic death in tumor cells.