Chemodynamic therapy (CDT) has emerged as an outstanding antitumor therapeutic method due to its selectivity and utilization of tumor microenvironment. However, there are still unmet requirements to achieve a high antitumor efficiency, including the tumor accumulation of catalyst and enrichment of reactants of Fenton reaction. Here, an iron-loaded semiconducting polymer dot modified with glucose oxidase (Pdot@Fe@GOx) is reported to deliver iron ions into tumor tissues and in situ generation of hydrogen peroxide in tumors. On one hand, Pdot@Fe@GOx converts glucose to gluconic acid and hydrogen peroxide (H2 O2 ) in tumor, which not only consumes glucose of tumor cells, but also provides the H2 O2 for the following Fenton reaction. On the other hand, the Pdot@Fe@GOx delivers active iron ions in tumor to perform CDT with the combination of the generated H2 O2 . In addition, the Pdot@Fe@GOx has both photothermal and photodynamic effects under the irradiation of near-infrared laser, which can improve and compensate the CDT effect to kill cancer cells. This Pdot@Fe@GOx-based multiple-mode therapeutic strategy has successfully achieved a synergistic anticancer effect with minimal side effects and has the potential to be translated into preclinical setting for tumor therapy.