Starvation therapy has shown promise as a cancer treatment, but its efficacy is often limited when used alone. In this work, a multifunctional nanoscale cascade enzyme system, named CaCO@MnO-NH@GOx@PVP (CMGP), was fabricated for enhanced starvation/chemodynamic combination cancer therapy. CMGP is composed of CaCO nanoparticles wrapped in a MnO shell, with glucose oxidase (GOx) adsorbed and modified with polyvinylpyrrolidone (PVP). MnO decomposes HO in cancer cells into O, which enhances the efficiency of GOx-mediated starvation therapy. CaCO can be decomposed in the acidic cancer cell environment, causing Ca overload in cancer cells and inhibiting mitochondrial metabolism. This synergizes with GOx to achieve more efficient starvation therapy. Additionally, the HO and gluconic acid produced during glucose consumption by GOx are utilized by MnO with catalase-like activity to enhance O production and Mn release. This process accelerates glucose consumption, reactive oxygen species (ROS) generation, and CaCO decomposition, promoting the Ca release. CMGP can alleviate tumor hypoxia by cycling the enzymatic cascade reaction, which increases enzyme activity and combines with Ca overload to achieve enhanced combined starvation/chemodynamic therapy. In vitro and in vivo studies demonstrate that CMGP has effective anticancer abilities and good biosafety. It represents a new strategy with great potential for combined cancer therapy.