Engineering Macrophages via Nanotechnology and Genetic Manipulation for Cancer Therapy

Xiaoling Ding,Lei Wu,Xiaorong Zhou,Guiping Yu,Xinchen Sun,Yu Zhao,Huihui Cai,Ying Liu,Dingjingyu Zhou

doi:10.3389/fonc.2021.786913

Abstract

Macrophages play critical roles in tumor progression. In the tumor microenvironment, macrophages display highly diverse phenotypes and may perform antitumorigenic or protumorigenic functions in a context-dependent manner. Recent studies have shown that macrophages can be engineered to transport drug nanoparticles (NPs) to tumor sites in a targeted manner, thereby exerting significant anticancer effects. In addition, macrophages engineered to express chimeric antigen receptors (CARs) were shown to actively migrate to tumor sites and eliminate tumor cells through phagocytosis. Importantly, after reaching tumor sites, these engineered macrophages can significantly change the otherwise immune-suppressive tumor microenvironment and thereby enhance T cell-mediated anticancer immune responses. In this review, we first introduce the multifaceted activities of macrophages and the principles of nanotechnology in cancer therapy and then elaborate on macrophage engineering via nanotechnology or genetic approaches and discuss the effects, mechanisms, and limitations of such engineered macrophages, with a focus on using live macrophages as carriers to actively deliver NP drugs to tumor sites. Several new directions in macrophage engineering are reviewed, such as transporting NP drugs through macrophage cell membranes or extracellular vesicles, reprogramming tumor-associated macrophages (TAMs) by nanotechnology, and engineering macrophages with CARs. Finally, we discuss the possibility of combining engineered macrophages and other treatments to improve outcomes in cancer therapy.

Highlights

Macrophages are a class of immune cells with highly diverse phenotypes and functions
In a typical inflammatory response caused by microorganisms, pathogen-derived molecules known as pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS) in bacterial wall, can be detected by macrophages through a group of receptors called pattern recognition receptors (PRRs), which triggers the activation of macrophages [5,6,7]
Ibarra et al prepared mouse bone marrow-derived monocytes and THP-1 cells loaded with polymer NPs, and they showed that NP loading had no significant effect on the viability and function of macrophages, nor did it affect the differentiation of THP-1 cells into macrophages upon stimulation with phorbol 12myristate 13-acetate (PMA)

Summary

INTRODUCTION

Macrophages are a class of immune cells with highly diverse phenotypes and functions. A series of studies have demonstrated that macrophages can be exploited as cell carriers to actively transport NPs into tumor sites [30, 87], and the following section will introduce the preparation, function, mechanisms, and limitations of NPL-Ms in cancer therapy. Ibarra et al prepared mouse bone marrow-derived monocytes and THP-1 cells loaded with polymer NPs, and they showed that NP loading had no significant effect on the viability and function of macrophages, nor did it affect the differentiation of THP-1 cells into macrophages upon stimulation with phorbol 12myristate 13-acetate (PMA). Because monocytes/macrophages efficiently phagocytose apoptotic bodies, Zheng et al intravenously injected light-sensitive gold NPs encapsulated by apoptotic bodies, which were quickly engulfed by macrophages, generating NPL-Ms in vivo These NPL-Ms effectively migrated to tumor sites and inhibited tumor growth and metastasis in a mouse tumor model [108].

Method Descriptions and Mechanisms

Limitations and Challenges

Findings

CONCLUSION AND PERSPECTIVE