Engineered IFN‐γ‐Expressing Platelet‐Like Microparticles Trigger Macrophage‐Targeted Immunity to Eradicate Liver Metastases

ABSTRACT Immunotherapy for colorectal cancer liver metastasis is often compromised by a highly immunosuppressive hepatic microenvironment characterized by tolerogenic macrophages that act as a systemic immune sink. Here, given the potent but systemically toxic antitumor profile of interferon‐γ (IFN‐γ), we engineered hepatic macrophage‐targeted cytokine‐expressing platelet‐like microparticles (HM‐CPMP) for the local delivery of IFN‐γ, thereby reprogramming the immune status of the liver. Mechanistically, HM‐CPMP treatment drove extensive M1‐like macrophage polarization and a CXCL9/10 chemotactic axis, which together shifted the liver from a tolerogenic to a pro‐inflammatory state. Therefore, systemic administration of HM‐CPMP facilitated the clearance of established liver metastases and conferred a marked survival benefit while strictly preserving systemic homeostasis. Intravital imaging revealed that this localized innate immune reprogramming broke the immunosuppressive tumor niche and recruited polyfunctional CXCR6 + and CD8 + T cells to eradicate metastatic cells. Collectively, by enabling precise hepatic immune modulation, the cytokine‐expressing platelet‐like microparticle delivery platform unleashes a potent localized antitumor response while preserving systemic homeostasis. Our findings provide a highly translational clinical strategy for biosynthetic cytokine‐based immunotherapy against liver metastases.