Ferroptosis to Pyroptosis Regulation by Iron-Based Nanocatalysts for Enhanced Tumor Immunotherapy

Immunogenic cell death serves as a pivotal mechanism in enhancing antitumor immunotherapy by engaging both innate and adaptive immune responses. However, a key unanswered question is which mode of cell death, particularly ferroptosis or pyroptosis, serves as the optimal pathway for activating the immune response. In this study, we introduce an innovative iron-based nanocatalytic medicine that strategically regulates ferroptosis to pyroptosis to augment antitumor immunotherapy. By harnessing the intricate interplay between iron and carbonyl cyanide m-chlorophenyl hydrazone (CP), we engineered the nanomedicine which is capable of regulating ferroptosis to the more immunogenic pyroptosis within tumor cells. In vitro analyses revealed that the treatment with CP-encapsulated iron-based nanomedicine (HFCP) can effectively induce pyroptosis of cancer cells, exhibiting greatly enhanced efficacy in eradicating tumor cells and stimulating immune responses compared to the ferroptosis-inducing counterpart without CP incorporation (iron alone). Resultantly, HFCP not only effectively inhibited primary tumor growth but also suppressed the growth of untreated distant tumors to a large extent, underscoring a notably induced immune memory. Taken together, these results indicate that HFCP-induced pyroptosis offers a significantly more powerful approach to tumor immunotherapy than ferroptosis, offering promising potentials for achieving long-term immunotherapeutic outcomes through the reversal of the immunosuppressive tumor microenvironment and the effective regulation of immunogenic cell death modes.