The effective deployment of reactive oxygen species (ROS)-mediated oncotherapy in practice remains challenging, mired by uncontrollable catalytic processes, stern reaction conditions and safety concerns. Herein, we develop a copper nanodot integrating sonodynamic and catalytic effects within one active center, which responds to exogenous ultrasound (US) and endogenous H2O2 stimuli. US irradiation induces the valence conversion from Cu(II) to Cu(I) catalyzing H2O2 into •OH for chemodynamic therapy. Meanwhile, valence transformation results in electron-hole pairs separation, promoting ROS generation for sonodynamic therapy. Notably, copper nanodots not only block lysosome fusion and degradation leading to autophagy flux blockage, but also interfere with the glutathione peroxidase 4 and cystine-glutamate antiporter SLC7A11 function achieving ferroptosis. Furthermore, reversible valence changes, inherent hydrophilicity and renal clearance ultrasmall size guarantee biosafety.