Reactive oxygen species (ROS) generating strategies have been widely adopted for cancer therapy, but therapeutic efficacies are often low due to the complicated tumor microenvironment. In this study, we present the development of tumor-targeting polymer nanohybrids that amplify ROS generation by combining photodynamic therapy (PDT) and chemodynamic therapy (CDT) for cancer treatment. Such polymer nanohybrids contained three main components: a semiconducting polymer (SP) that acted as the photosensitizer for PDT, manganese dioxide (MnO2) that acted as the catalyst for CDT, and transferrin that mediated tumor targeting via binding to transferrin receptors overexpressed on the surface of tumor cells. The formed nanohybrids (TSM) showed obviously enhanced accumulation efficacy in tumor sites because of their targeting ability. In tumor sites, TSM produced singlet oxygen (1O2) under near-infrared (NIR) laser irradiation and a hydroxyl radical (˙OH) via reacting with hydrogen peroxide (H2O2), which resulted in amplified generation of ROS to achieve PDT/CDT combinational therapy. The growth of subcutaneous 4T1 tumors was remarkably inhibited via TSM-mediated treatment. In addition, this therapeutic efficacy could suppress tumor metastasis in the liver and lungs. This study presents a targeting hybrid nanoplatform to combine different ROS generating strategies for effective cancer therapy.