Engineering Macrophages via Nanotechnology and Genetic Manipulation for Cancer Therapy

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.

Natural products targeting macrophages in tumor microenvironment are a source of potential antitumor agents

“…However, due to unclear target and off-target toxicity, it is particularly important to design some drug delivery systems improving the targetability and toxicity of compounds. Nanotechnology provides great opportunities for targeted regulation of macrophages polarization, which could improve cancer immunotherapy (Ding et al, 2021). Immunostimulation usually starts from the interaction between nanocarriers and innate immune cells such as macrophages (Andon et al, 2017).…”

The Progress and Prospects of Immune Cell Therapy for the Treatment of Cancer

“…The ECM creates a physical barrier for various anti-cancer therapies. However, macrophages play a crucial role in regulating the ECM and exhibit tumor-homing behavior 187 . CAR-engineered macrophages were shown to actively migrate to tumor sites, could locally deliver cytokines and/or cytotoxic substances to antigen-specific environments when used as a drug delivery system, significantly alter the immune-suppressive TME and eliminate tumor cells through phagocytosis 187 , 188 .…”

“…However, macrophages play a crucial role in regulating the ECM and exhibit tumor-homing behavior 187 . CAR-engineered macrophages were shown to actively migrate to tumor sites, could locally deliver cytokines and/or cytotoxic substances to antigen-specific environments when used as a drug delivery system, significantly alter the immune-suppressive TME and eliminate tumor cells through phagocytosis 187 , 188 . Zhang et al 189 used CAR-modified macrophages to solve the problem of insufficient immune cell infiltration into tumors caused by the ECM.…”

Tumor-associated macrophages: Prognostic and therapeutic targets for cancer in humans and dogs

“…Combining cell therapy with nanotechnology has been used in of interesting ways to target TAMs. The first approach is to load M1-like macrophages with a variety of drug-laden NPs, inducing tumor cell killing via both the NP load and their natural M1 functions ( 255 , 256 ). The second approach involves using NPs to deliver messages to TAMs to induce repolarization.…”