A RIG-I targeting nanozyme induces PANoptosis for cancer immunotherapy.

Abstract

The emerging concept of PANoptosis-a lytic cell death pathway integrating apoptosis, pyroptosis, and necroptosis-presents avenues for cancer immunotherapy, yet its therapeutic exploitation remains limited by undefined molecular sensors and induction strategies. Here, we report a tumor-targeting nanozyme, Hemin-His-Mn, that concurrently activates retinoic acid-inducible gene I-mediated PANoptosome assembly and catalyzes reactive oxygen species amplification to achieve precision PANoptosis induction. Mechanistically, Hemin-His-Mn binds to retinoic acid-inducible gene I and alleviates its autoinhibition, initiating PANoptosome formation through the orchestrated recruitment of cell death executioners, thereby identifying retinoic acid-inducible gene I as a master PANoptosis sensor. In parallel, Hemin-His-Mn exerts peroxidase-like activity to generate cytotoxic reactive oxygen species surges, facilitating complete execution of PANoptosis. This dual mechanism promotes potent immunogenicity by releasing damage-associated molecular patterns and enhancing antigen presentation, ultimately eliciting robust T cell-mediated antitumor immunity. In multiple male mouse preclinical models, Hemin-His-Mn reprograms the tumor immune microenvironment and synergizes with immune checkpoint inhibitors. Our study introduces a retinoic acid-inducible gene I-targeting nanotechnology platform that redefines strategies for PANoptosis induction, provides mechanistic insights into PANoptosome assembly, and offers a clinically translatable modality for enhancing cancer immunotherapy.