Engineering Macrophages for Cancer Immunotherapy and Drug Delivery

Abstract

was that most nanoparticles do not have a sufficiently long blood half-life and cannot realize deep penetration in tumor tissue. Thus, recent progress in the development of strategies for mimicking or modulating cells offers a highly attractive alternative to drug delivery. [10-17] As natural immune cells and antigenpresenting cells, macrophages [18] have a long blood half-life and can specifically bind to tumor tissue. Therefore, applying macrophages in chemical drug delivery would lead to a significant increase in drug accumulation in tumors. Since macrophages can engulf foreign particles in nature, they can directly phagocytose drugs and then deliver drugs to tumors. [19] Thus, live macrophages may serve as drug carriers. To further increase the tumor-targeting ability of macrophages, they can be engineered with targeting ligands. [20] In addition, learning from red blood cell (RBC) membrane coating technology, [21-23] a macrophage cell membrane coating was developed and it resulted in enhanced tumor uptake of drugs. On the other hand, macrophages play an important role in modulating the tumor immune microenvironment. M1 macrophages inhibit tumor growth, while M2 macrophages promote tumor growth. Inhibition of M2 macrophages and repolarization of M2 macrophages to M1 macrophages are common strategies to treat solid tumors. Furthermore, since these macrophages express SIRPα on their surface, their phagocytic activity against CD47-expressing tumor cells is significantly affected by the CD47-SIRPα pathway. Therefore, blocking the CD47-SIRPα pathway can further enhance the anti-tumor efficacy of macrophages. Herein, to elucidate the importance of macrophages in tumor therapy (Figure 1), we will first discuss the role of macrophages in cancer immunotherapy, including the inhibition, depletion, and repolarization of tumor-associated macrophages (TAMs) and the blocking of the CD47-SIRPα pathway to enhance phagocytosis in tumor therapy. Then, based on the tumor targeting of M1 macrophages, we will discuss the applications of macrophages, macrophage-derived exosomes, and macrophage-coated NPs for drug delivery. We will thus offer a comprehensive understanding of functionalizing macrophages for tumor therapy. Macrophages play an important role in cancer development and metastasis. Proinflammatory M1 macrophages can phagocytose tumor cells, while antiinflammatory M2 macrophages such as tumor-associated macrophages (TAMs) promote tumor growth and invasion. Modulating the tumor immune microenvironment through engineering macrophages is efficacious in tumor therapy. M1 macrophages target cancerous cells and, therefore, can be used as drug carriers for tumor therapy. Herein, the strategies to engineer macrophages for cancer immunotherapy, such as inhibition of macrophage recruitment, depletion of TAMs, reprograming of TAMs, and blocking of the CD47-SIRPα pathway, are discussed. Further, the recent advances in drug delivery using M1 macrophages, macrophage-derived exosomes, and macrophage-membrane-coated nanoparticles are ela...

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