Background: Though nanomedicine-based photothermal therapy (PTT) has demonstrated promising prospect in tumor treatment due to its high therapeutic efficiency and controllable range, the overexpression of heat shock proteins (HSPs) during PTT can lead to intracellular thermal resistance and reduce its effectiveness. Reactive oxygen species (ROS), followed by the application of chemodynamic therapy (CDT) and photodynamic therapy (PDT), can eliminate HSPs and overcome thermal resistance. However, the tumor microenvironment, including hypoxia and glutathione (GSH) overexpression, impedes the production of ROS and therapeutic efficacy of CDT and PDT. Therefore, we proposed a multifunctional nanoplatform (HMPB@TCPP-Cu) driving PTT/ PDT/ CDT synergistic therapy for tumor treatment via modulating ROS and HSPs. Methods and Results: In this work, a novel nanoplatform (HMPB@TCPP-Cu) composed of O2/PTT supplier HMPB (hollow mesoporous Prussian blue) and the loaded PDT/CDT agent (TCPP-Cu2+) was prepared. HMPB acts as an photothermal converter, effectively raising the tumor temperature and inducing apoptosis. HMPB is also a potent catalase-like nanozyme, which can catalyze hydrogen peroxide into oxygen and reduce tumor hypoxia, thus elevating the efficiency of ROS production and the effectiveness of PDT with the wing of sonosensitizer-TCPP. The intracellular glutathione(GSH) was depleted by Cu2+ and •OH was generated along with the Cu2+/Cu+ converting and Cu+-mediated Fenton-like reaction. Subsequently, the increased levels of ROS effectively eliminate intratumoral thermal resistance. The HMPB@TCPP-Cu has achieved synergistic PTT/PDT/CDT for hepatoblastoma treatment and significant inhibition of tumor growth was detected both in vitro and in vivo. Conclusion: This study presents a multifunctional nanoplatform that combines photothermal/ chemodynamic/ photodynamic therapy for efficient hepatoblastoma treatment via modulating ROS and HSPs. Collectively, this study provides an appealing strategy in the cleavage of thermal resistance and a novel assistance and enhancement on thermal-related therapies.