Although oxidative stress-based antitumor modality derived from reactive oxygen species (ROS) storm has attracted considerable attention in copper-based nanomaterials, its efficiency is still weakened by the insufficient hydrogen peroxide (H2O2) and overexpressed glutathione (GSH) in a tumor microenvironment (TME). In view of this, we designed an engineered programmable spike-like nanogenerator via the coordination-driven co-assembly of Evans Blue (EB), copper ions (CuII), and 5-hydroxy-p-naphthoquinone (HND). For programmable nanogenerators, the introduction of EB as a stabilizer-like component can not only adjust its morphology but also achieve its visual tracking. Interestingly, such programmable nanogenerators can be efficiently enriched in tumor regions and then internalized into tumor cells due to ECH with spike-like morphology. Notably, once the nanogenerator is disintegrated and burst to release the drug upon acidic lysosome and endogenous GSH triggering, the released HND can not only efficiently amplify endogenous H2O2 by intracellular oxidoreductases but also down-regulate the peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin 1) activity. In addition, the released CuII ions can efficiently catalyze the degradation of the endogenous H2O2 to amplify hydroxyl radicals (˙OH) and down-regulate the overexpressed GSH to reduce ˙OH elimination for on-demand cascade-amplifying oxidative stress. Importantly, such programmable nanogenerators show an excellent antitumor effect via down-regulating the Pin 1 activity and cascade-amplifying oxidative stress. In this study, we propose a spatiotemporally programmable cascade nanogenerator for oxidative stress-based antitumor therapy.