A Magnetic Resonance Imaging Reportable Strategy for In Situ CuET and Mn ²⁺ Generation to Boost Antitumor Immunity

ABSTRACT Repurposing the alcohol‐aversion drug disulfiram (DSF) for cancer therapy has gained momentum, with its metabolite diethyldithiocarbamate (DDTC) 2 ‐copper complex (CuET) identified as the key anticancer agent. While nanosystems enabling CuET generation in tumors have been developed, noninvasive tools to monitor CuET formation without limitation of image depth remain lacking, impeding clinical translation. Herein, we report a sequential administration strategy that integrates in situ CuET generation with Mn 2+ mediated magnetic resonance imaging (MRI) reporting. In detail, MnDDTC 3 ‐loaded DSPE‐PEG nanoparticles (MDDP) accumulate in tumors via the enhanced permeability and retention (EPR) effect. Subsequent systemic CuCl 2 administration triggers a tumor‐localized reaction to generate CuET and release Mn 2+ . The released Mn 2+ enhances T 1 ‐weighted MRI signals, providing real‐time confirmation of CuET formation. Mechanistically, this reaction induces a “low‐to‐high toxicity” transition, disrupting mitochondrial function to trigger cuproptosis and apoptosis in 4T1 cancer cells. Mitochondrial dysfunction releases mtDNA to activate the cGAS‐STING pathway and induces immunogenic cell death (ICD), which synergistically enhances antitumor immunity through dendritic cell maturation, macrophage repolarization, T cell activation, and establishment of immune memory. This reportable strategy not only addresses the critical need for monitoring in vivo CuET generation but also reinforces tumor immunotherapy, offering a translatable paradigm for theranostic cancer treatment.