The production of reactive oxygen species (ROS) is susceptible to external excitation or insufficient supply of related participants (, hydrogen peroxide (HO) and sensitizer), liming ROS-driven tumor treatment. Additionally, the lysosomal retention effect severely hinders the utilization of ROS-based nanosystems and severely restricted the therapeutic effect of tumors. Therefore, first reported herein an intelligent nanocatalyst, TCPP-Cu@MnO ((Mn)(Mn)(Mn)O), and proposed a programmed ROS amplification strategy to treat tumors. Initially, the acidity-unlocked nanocatalyst was voluntarily triggered to generate abundant singlet oxygen (O) to mediate acid lysosomal ablation to assist nanocatalyst escape and partially induce lysosomal death, a stage known as lysosome-driven therapy. More unexpectedly, the high-yielding production of O in acid condition (pH 5.0) was showed compared to neutral media (pH 7.4), with a difference of about 204 times between the two. Subsequently, the escaping nanocatalyst further activated HO-mediated O and hydroxyl radical (•OH) generation and glutathione (GSH) consumption for further accentuation tumor therapy efficiency, which is based on the Fenton-like reaction and Russell reaction mechanisms. Therefore, in this system, a program-activatable TCPP-Cu@MnO nanocatalyst, was proposed to efficiently destruct organelle-lysosome O inducing, and stimulated HO conversion into highly toxic O and •OH in cytoplasm, constituting an attractive method to overcome limitations of current ROS treatment.