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Abstract

Pyroptosis, which rapidly releases cellular contents through pyroptotic pores, is an ideal method for inducing in situ cancer vaccines, evoking systemic antitumor immunity, and suppressing primary and metastatic tumors. However, the clinical translation of pyroptosis-based therapy is hindered by the inability to spatially control the activation of inert precursors and the inefficient catalytic activity of nanozymes, which often fail to generate sufficient reactive oxygen species for effective treatment. To address this, we designed a conductive coordination nanozyme prodrug, Cu–DHN. Its π-conjugated polyphenol backbone functions as an intrinsic “electron highway,” enabling rapid electron shuttling to utilize the entire nanoparticle volume for catalysis, thereby achieving exceptional peroxidase-like activity. Upon systemic administration, Cu–DHN remains inert in circulation but is precisely activated within the tumor microenvironment by a tandem GSH-depletion and H 2 O 2 -responsive logic gate. This triggers a self-cascade reaction that locally transforms the coordinated prodrug into juglone, which concurrently reverses gasdermin D epigenetic silencing and activates the NLRP3 inflammasome for caspase-1-mediated cleavage. This single-agent, tumor-specific initiation of pyroptosis, augmented by concomitant cuproptosis, elicits potent immunogenic cell death and robust systemic antitumor immunity, effectively suppressing primary and metastatic tumors while exhibiting a pristine safety profile. Our work establishes electron-shuttling coordination polymers as a versatile platform for developing safe and potent catalytic immunotherapies.