Multifunctional Superparamagnetic Copper Iron Oxide Nanoparticles for Synergistic Cancer Therapy via Magnetic Hyperthermia, Oxidative Stress and Immune Reprogramming

Abstract Aggressive cancers, characterized by high metastatic potential and resistance to conventional therapies, present a significant challenge in oncology. Current treatments often fail to effectively target metastasis, recurrence, and the immunosuppressive tumor microenvironment, while causing significant off‐target toxicity. Here, superparamagnetic copper iron oxide nanoparticles (SCIONs) as a multifunctional platform that integrates magnetic hyperthermia therapy, immune modulation, and targeted chemotherapeutic delivery, aiming to provide a more comprehensive cancer treatment is presented. Specifically, SCIONs generate localized hyperthermia under an alternating magnetic field while delivering a copper‐based anticancer agent, resulting in a synergistic anticancer effect. The hyperthermia induced by SCIONs caused ER stress and ROS production, leading to significant tumor cell death, while the copper complex further enhanced oxidative stress, ferroptosis, and apoptosis. Beyond direct cytotoxicity, SCIONs disrupted the tumor microenvironment by inhibiting cancer‐associated fibroblasts, downregulating epithelial‐mesenchymal transition markers, and reducing cell migration and invasion, thereby limiting metastasis. Additionally, SCION‐based therapy reprogrammed the immune microenvironment by inducing immunogenic cell death and enhancing dendritic cell activation, resulting in increased CD8+ T cell infiltration and amplified antitumor immunity. This integrated approach targets primary and metastatic tumors while mitigating immunosuppression, offering a promising next‐generation therapy for combating cancer with enhanced efficacy and reduced side effects.