Anti-Tumor Strategies by Harnessing the Phagocytosis of Macrophages

Abstract

Macrophages are essential for the human body in both physiological and pathological conditions, engulfing undesirable substances and participating in several processes, such as organism growth, immune regulation, and maintenance of homeostasis. Macrophages play an important role in anti-bacterial and anti-tumoral responses. Aberrance in the phagocytosis of macrophages may lead to the development of several diseases, including tumors. Tumor cells can evade the phagocytosis of macrophages, and "educate" macrophages to become pro-tumoral, resulting in the reduced phagocytosis of macrophages. Hence, harnessing the phagocytosis of macrophages is an important approach to bolster the efficacy of anti-tumor treatment. In this review, we elucidated the underlying phagocytosis mechanisms, such as the equilibrium among phagocytic signals, receptors and their respective signaling pathways, macrophage activation, as well as mitochondrial fission. We also reviewed the recent progress in the area of application strategies on the basis of the phagocytosis mechanism, including strategies targeting the phagocytic signals, antibody-dependent cellular phagocytosis (ADCP), and macrophage activators. We also covered recent studies of Chimeric Antigen Receptor Macrophage (CAR-M)-based anti-tumor therapy. Furthermore, we summarized the shortcomings and future applications of each strategy and look into their prospects with the hope of providing future research directions for developing the application of macrophage phagocytosis-promoting therapy.

Keywords: CAR-macrophage; immunotherapy; macrophages; nanomedicine; phagocytic signals.

Figure 1

Phagocytosis process of macrophages. After particle ligands bind to phagocytic receptors, macrophages engulf the particle in a process involving actin assembly, pseudopod extension, and phagosome closure. The phagosome fuses with the lysosome and becomes a phagolysosome, where particle digestion takes place.

Figure 2

Interactions between macrophages and tumor cells in FcγR-mediated phagocytosis. The phagocytosis of macrophages is related to phagocytic signals, phagocytic receptors, and macrophage activators. Phagocytic signals, including “eat me” signals (a), “don’t eat me” signals (b), and “find me” signals (c), function as phagocytosis switches. Macrophages recognize phagocyte-specific antigens and ligands through various phagocytic receptors (d). The capability of macrophage-mediated phagocytosis is influenced by macrophage activation (e).

Figure 3

Strategies for strengthening macrophage-mediated phagocytosis based on phagocytosis signal regulation. To promote macrophage-mediated phagocytosis, “don’t eat me” signals are blocked using monospecific or bispecific antibodies (a), small molecule drugs (b), and peptides (c). Nanomaterials such as liposomes, exosomes, and nanoparticles are used as drug delivery systems (d) to carry therapeutics that encourage macrophage phagocytosis by blocking “don’t eat me” signals. (e) In magneto thermodynamic therapy, an increased level of ROS induces expression of the “eat me” signal CRT on tumor cells, which enhances macrophage-mediated phagocytosis. (f) Under LED irradiation, photosensitizers increase CRT on the surface of tumor cells, resulting in macrophage-mediated phagocytosis of tumor cells.

Figure 4

Strategies for strengthening macrophage-mediated phagocytosis based on phagocytosis ability regulation. (a) Using tumor-specific mAbs as ACDP-potentiating agents to induce macrophage-mediated ADCP. (b) Using macrophage activators to switch macrophages into a phenotype with greater capacity to phagocytose tumor cells. (c) Macrophages are collected from tumor patients’ blood and are designed to express CARs. After cell expansion, CAR-Ms are given back to patients through infusion. CARs detect and bind to targeted antigens on tumor cells, resulting in enhanced macrophage phagocytosis.

Figure 5

Current challenges and future perspectives for the application of macrophage phagocytosis-promoting therapy. (a) Off-target harm leads to adverse effects and raises safety concerns, which raises the demand for higher targeting specificity. (b) The short half-life period of drugs or CAR-Ms results in limited effects on promoting macrophage phagocytosis. Delivery systems are needed to prolong the circulation time of drugs and CAR-Ms. (c) Abnormal vessels cause poor penetration of drugs and CAR-Ms into solid tumors, which can be facilitated by vessel normalization. (d) The limited efficiency of harnessing macrophage-mediated phagocytosis can be improved by combination therapy.