Chemodynamic therapy (CDT) has attracted increasing attention in tumor treatment but is limited by insufficient endogenous HO. Moreover, it is challenging for monotherapy to achieve a satisfactory outcome due to tumor complexity. Herein, we developed an intelligent nanoplatform that could respond to a tumor microenvironment to induce efficient CDT without complete dependence on HO and concomitantly generate chemotherapy and oncosis therapy (OT). The nanoplatform was constructed by a calcium- and iron-doped mesoporous silica nanoparticle (CFMSN) loaded with dihydroartemisinin (DHA). After entering into cancer cells, the nanoplatform could directly convert the intracellular HO into toxic •OH due to the Fenton-like activity of CFMSN. Meanwhile, the acidic microenvironment and endogenous chelating molecules triggered Ca and Fe release from the nanoplatform, causing particle collapse with accompanying DHA release for chemotherapy. Simultaneously, the released Ca induced intracellular Ca-overloading for OT, which was further enhanced by DHA, while the released Fe was reduced to reactive Fe by intracellular glutathione, guaranteeing efficient Fenton reaction-mediated CDT. Moreover, Fe cleaved the peroxy bonds of DHA to generate C-centered radicals to further amplify CDT. Both in vitro and in vivo results confirmed that the nanoplatform exhibited excellent anticancer efficacy via the synergistic effect of multi therapeutic modalities, which is extremely promising for high-efficient cancer therapy.