Synergistic cancer starvation/ROS-mediated/chemo-therapy is developed through a cascade reaction with enzyme glucose oxidase (GOX) modified on the surface of an Fe-based metal organic framework (MOF(Fe)) and drug camptothecin (CPT) loaded into the cavities of MOF(Fe). Once internalized by tumor cells, GOX catalyzes endogenous glucose into hydrogen peroxide (H2O2) and gluconic acid (H+) enabling starvation therapy through choking off energy (glucose) supply. Meanwhile, the acidic micro-environment of tumor enhanced by the generated H+ degrades the MOF(Fe) simultaneously releasing CPT for chemotherapy and Fe3+, catalyzing H2O2 into one of the strongest reactive oxygen species (ROS) ˙OH enabling ROS-mediated therapy. Both in vitro and in vivo results show remarkable tri-modal synergistic anticancer effects. This work may shed some light on the development of novel multi-modal cancer therapies without any external intervention.