A self-amplifying ROS-responsive nanoplatform for simultaneous cuproptosis and cancer immunotherapy was developed to enhance the efficacy of elesclomol (ES), a copper ionophore that induces cell death via cuproptosis. The nanoplatform, ECPCP, was designed to encapsulate ES-Cu compound (EC) within a ROS-responsive polymer (PCP) based on cinnamaldehyde (CA) and polyethylene glycol (PEG). This design significantly prolonged the systemic circulation of EC and improved its tumor accumulation. Upon cellular internalization, the PCP coating dissociated in response to high levels of ROS, releasing ES and Cu, which triggered cuproptosis. Additionally, Cu²⁺-stimulated Fenton-like reactions and CA-stimulated ROS production disrupted redox homeostasis, inducing immunogenic cell death (ICD) and enhancing antitumor immune responses. The excessive ROS also accelerated the dissociation of ECPCP, forming a positive feedback loop that amplified the therapeutic effect. ECPCP effectively induced tumor cell death through cuproptosis and ICD, leading to increased tumor cell apoptosis, enhanced immune cell activation, and improved antitumor efficacy. In vivo studies demonstrated that ECPCP significantly inhibited tumor growth and improved survival rates in mice, with minimal toxicity. The nanoplatform showed promising potential for clinical application as a dual therapy for cancer.A self-amplifying ROS-responsive nanoplatform for simultaneous cuproptosis and cancer immunotherapy was developed to enhance the efficacy of elesclomol (ES), a copper ionophore that induces cell death via cuproptosis. The nanoplatform, ECPCP, was designed to encapsulate ES-Cu compound (EC) within a ROS-responsive polymer (PCP) based on cinnamaldehyde (CA) and polyethylene glycol (PEG). This design significantly prolonged the systemic circulation of EC and improved its tumor accumulation. Upon cellular internalization, the PCP coating dissociated in response to high levels of ROS, releasing ES and Cu, which triggered cuproptosis. Additionally, Cu²⁺-stimulated Fenton-like reactions and CA-stimulated ROS production disrupted redox homeostasis, inducing immunogenic cell death (ICD) and enhancing antitumor immune responses. The excessive ROS also accelerated the dissociation of ECPCP, forming a positive feedback loop that amplified the therapeutic effect. ECPCP effectively induced tumor cell death through cuproptosis and ICD, leading to increased tumor cell apoptosis, enhanced immune cell activation, and improved antitumor efficacy. In vivo studies demonstrated that ECPCP significantly inhibited tumor growth and improved survival rates in mice, with minimal toxicity. The nanoplatform showed promising potential for clinical application as a dual therapy for cancer.