Boosting Doxil Chemoimmunotherapy via Macrophage Repolarization with Metformin Microparticles

Abstract

Insufficient tumor accumulation and distribution, as well as low antitumor immunity and enriched M2-like tumor-associated macrophages (TAMs) severely limit the therapeutic efficacy of liposomal doxorubicin (Doxil). Here, mannose-engineered macrophage-derived microparticles loading metformin ( [email protected] ) efficiently repolarize Doxil-enriched M2-like TAMs to M1-like phenotype. Doxil elicits immunogenic cell death (ICD) of tumor cells and activates STING pathway to facilitate the phagocytosis of tumor cells by [email protected] M2-like TAMs, contributing to macrophage maturation and CD8 + T cell activation. In addition, [email protected] efficiently increase the tumor accumulation and penetration of Doxil. Thus, combination treatment of [email protected] and Doxil generates strong anticancer activity and long-term antitumor immune memory against tumor recurrence. Our results demonstrate that [email protected] are the potential candidates to improve Doxil chemoimmunotherapy in cancer treatment.