Ferroptosis to Pyroptosis\nRegulation by Iron-Based\nNanocatalysts for Enhanced Tumor Immunotherapy

Immunogenic cell death serves as a pivotal mechanism\nin enhancing\nantitumor immunotherapy by engaging both innate and adaptive immune\nresponses. However, a key unanswered question is which mode of cell\ndeath, particularly ferroptosis or pyroptosis, serves as the optimal\npathway for activating the immune response. In this study, we introduce\nan innovative iron-based nanocatalytic medicine that strategically\nregulates ferroptosis to pyroptosis to augment antitumor immunotherapy.\nBy harnessing the intricate interplay between iron and carbonyl cyanide <i>m</i>-chlorophenyl hydrazone (CP), we engineered the nanomedicine\nwhich is capable of regulating ferroptosis to the more immunogenic\npyroptosis within tumor cells. In vitro analyses revealed that the\ntreatment with CP-encapsulated iron-based nanomedicine (HFCP) can\neffectively induce pyroptosis of cancer cells, exhibiting greatly\nenhanced efficacy in eradicating tumor cells and stimulating immune\nresponses compared to the ferroptosis-inducing counterpart without\nCP incorporation (iron alone). Resultantly, HFCP not only effectively\ninhibited primary tumor growth but also suppressed the growth of untreated\ndistant tumors to a large extent, underscoring a notably induced immune\nmemory. Taken together, these results indicate that HFCP-induced pyroptosis\noffers a significantly more powerful approach to tumor immunotherapy\nthan ferroptosis, offering promising potentials for achieving long-term\nimmunotherapeutic outcomes through the reversal of the immunosuppressive\ntumor microenvironment and the effective regulation of immunogenic\ncell death modes.