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.