Hypoxia-induced multi-drug resistance (MDR) often develops in the chemotherapy process of most anticancer drugs ( e.g. , doxorubicin, DOX) and results in treatment failure in the clinic. Herein, a PEG-Pt(IV) prodrug was co-self-assembled with DOX into nanodrugs (PEG-Pt(IV)@DOX NPs). They can accumulate in tumor sites due to their longer blood retention half-life. Under light irradiation, the PEG-Pt(IV) prodrug can in situ self-generate oxygen (O 2 ) to reduce the hypoxic zone in tumor tissue effectively and simultaneously release active cis -Pt(II) and DOX. The increasing O 2 concentration in the tumor tissue can raise the level of reactive oxygen species (ROS) produced from DOX and significantly enhance the cytotoxicity of DOX to inhibit tumor proliferation by combining with active cis -Pt(II). Finally, the hypoxia-induced MDR of DOX can be alleviated. More importantly, the enhanced cytotoxicity of DOX is limited to the tumor site, which can effectively reduce its side effects on normal tissues. In summary, this would be a promising platform for the combination chemotherapy of hypoxia solid tumors in the clinic.