Sequential Magneto‐Activation Platforms Break Multiple Cellular Defenses to Potentiate Mildthermal‐Oxidative‐Immunotherapeutics

ABSTRACT Cancer cells develop defense mechanisms to realize self‐protection. The intrinsic and adaptive defenses involve thermoresistance, redox homeostasis, and immunosuppressive microenvironments, which compromise the efficacy of therapeutic interventions. Aiming to break these cellular defenses collectively, the sequential magneto‐activation strategy has been proposed, as a contrast to direct magneto‐activation, by empowering the platform with thermal‐oxidative‐immunotherapeutic augmentation. The platform consists of core‐shell magnetic nanoparticles loaded with model inhibitors of L‐buthionine sulfoximine and gambogic acid and sealed with phase‐change materials. Upon low‐intensity alternating magnetic field (AMF) irradiation, the platform generates low local heat to unlock inhibitors, downregulating thermoresistance proteins and redox homeostasis in cancer cells. The subsequent high‐intensity AMF activation exhibits a higher mildthermal‐oxidative efficacy than direct activation, which causes potent immunogenic cell death for T cell expansion and tumor‐associated macrophage polarization. Importantly, the platform in combination with immune checkpoint inhibitors prominently suppresses bilateral tumor proliferation with the infiltration of multiple immune cells, and retard lung metastasis. This work validates the significance of the sequential magneto‐activation strategy and offers insights into immune rejuvenation against metastasis.