Nanotheranostic platforms, which can respond to tumor microenvironments (TME, such as low pH and hypoxia), are immensely appealing for photodynamic therapy (PDT). However, hypoxia in solid tumors harms the treatment outcome of PDT which depends on oxygen molecules to generate cytotoxic singlet oxygen (O). Herein, we report the design of TME-responsive smart nanotheranostic platform (DOX/ZnO@Zr-Ce6/Pt/PEG) which can generate endogenously hydrogen peroxide (HO) and oxygen (O) to alleviate hypoxia for improving photodynamic-chemo combination therapy of tumors. DOX/ZnO@Zr-Ce6/Pt/PEG nanocomposite was prepared by the synthesis of ZnO nanoparticles, in-situ assembly of Zr-Ce6 as typical metal-organic framework (MOF) on ZnO surface, in-situ reduction of Pt nanozymes, amphiphilic lipids surface coating and then doxorubicin (DOX) loading. DOX/ZnO@Zr-Ce6/Pt/PEG nanocomposite exhibits average sizes of ∼78 nm and possesses a good loading capacity (48.8 %) for DOX. When DOX/ZnO@Zr-Ce6/Pt/PEG dispersions are intratumorally injected into mice, the weak acidic TEM induces the decomposition of ZnO core to generate endogenously HO, then Pt nanozymes catalyze HO to produce O for alleviating tumor hypoxia. Upon laser (630 nm) irradiation, the Zr-Ce6 component in DOX/ZnO@Zr-Ce6/Pt/PEG can produce cytotoxic O, and O generation rate can be enhanced by 2.94 times due to the cascaded generation of endogenous HO/O. Furthermore, the generated O can suppress the expression of hypoxia-inducible factor α, and further enable tumor cells to become more sensitive to chemotherapy, thereby leading to an increased effectiveness of chemotherapy treatment. The photodynamic-chemo combination therapy from DOX/ZnO@Zr-Ce6/Pt/PEG nanoplatform exhibits remarkable tumor growth inhibition compared to chemotherapy or PDT. Thus, the present study is a good demonstration of a TME-responsive nanoplatform in a multimodal approach for cancer therapy.