Boosting doxil-based chemoimmunotherapy via reprogramming tumor-associated macrophages

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 (Met@Man-MPs) 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 Met@Man-MPs-repolarized M2-like TAMs, contributing to macrophage maturation and CD8+ T cell activation. In addition, Met@Man-MPs efficiently increase the tumor accumulation and penetration of Doxil. Thus, combination treatment of Met@Man-MPs and Doxil generates strong anticancer activity and long-term antitumor immune memory against tumor recurrence. Our results demonstrate that Met@Man-MPs are the potential candidates to improve Doxil chemoimmunotherapy in cancer treatment.