Chemodynamic therapy (CDT), which employs Fenton/Fenton-like agents to decompose hydrogen peroxide (H₂O₂) into toxic hydroxyl radical (•OH) to induce cancer cell apoptosis and necrosis, holds great promise in tumor therapy due to its high selectivity. Nevertheless, its efficiency is impaired by the insufficient intracellular H₂O₂ concentration and/or the insensitive response of Fenton/Fenton-like agents to the slightly acid tumor microenvironment (pH∼7.0–6.5). Herein, we develop a novel CDT reagent based on CeO₂ quantum dot (QD) decorated MgO₂ nanosheets engineered with cascade reactions to boost the intracellular H₂O₂ level and high pH-activated (pH = 6.5) characteristic for an enhanced CDT. Under the tumor microenvironment (pH = 6.5), MgO₂ nanosheets that are highly reactive can react with H₂O to produce nontoxic Mg²⁺ and abundant H₂O₂, boosting the intracellular H₂O₂ level. The self-generated H₂O₂ is subsequently converted into •OH by CeO₂ QD, which is served as a relatively high pH-activated (pH = 6.5) Fenton-like agent. The sufficient intracellular H₂O₂ supply and sensitive response to the slightly acid tumor sites significantly improve the Fenton reaction, leading to the excellent in vivo CDT results with tumor growth inhibition effect. Our work presents a distinctive paradigm for self-boosting CDT efficacy.