A RIG-I targeting nanozyme induces PANoptosis for cancer immunotherapy

Area of Science:

• Biomedical Engineering
• Immunology
• Oncology

Background:

• PANoptosis, a cell death pathway integrating apoptosis, pyroptosis, and necroptosis, offers potential for cancer immunotherapy.
• Current limitations include undefined molecular sensors and induction strategies for PANoptosis.

Purpose of the Study:

• To develop a novel nanozyme, Hemin-His-Mn, for precise induction of PANoptosis.
• To elucidate the mechanism of Hemin-His-Mn in activating PANoptosis via retinoic acid-inducible gene I (RIG-I).
• To evaluate the therapeutic potential of Hemin-His-Mn in preclinical cancer models.

Main Methods:

• Development of a tumor-targeting nanozyme, Hemin-His-Mn.
• Investigation of Hemin-His-Mn's interaction with RIG-I to induce PANoptosome assembly.
• Assessment of Hemin-His-Mn's peroxidase-like activity for reactive oxygen species generation.
• Evaluation of Hemin-His-Mn's efficacy in preclinical mouse models, including combination therapy with immune checkpoint inhibitors.

Main Results:

• Hemin-His-Mn activates RIG-I, initiating PANoptosome formation and identifying RIG-I as a key PANoptosis sensor.
• The nanozyme generates cytotoxic reactive oxygen species, ensuring complete PANoptosis execution.
• Hemin-His-Mn treatment enhanced immunogenicity by releasing DAMPs and improving antigen presentation.
• In preclinical models, Hemin-His-Mn reprogrammed the tumor immune microenvironment and showed synergy with immune checkpoint inhibitors.

Conclusions:

• Hemin-His-Mn represents a nanotechnology platform for targeted PANoptosis induction.
• The study provides mechanistic insights into PANoptosis regulation by RIG-I.
• This approach offers a clinically translatable strategy for enhancing cancer immunotherapy.