Macrophage-Mediated Tumor Cell Phagocytosis: Opportunity for Nanomedicine Intervention

Abstract

Macrophages are one of the most abundant non-malignant cells in the tumor microenvironment, playing critical roles in mediating tumor immunity. As important innate immune cells, macrophages possess the potential to engulf tumor cells and present tumor-specific antigens for adaptive antitumor immunity induction, leading to growing interest in targeting macrophage phagocytosis for cancer immunotherapy. Nevertheless, live tumor cells have evolved to evade phagocytosis by macrophages via the extensive expression of anti-phagocytic molecules, such as CD47. In addition, macrophages also rapidly recognize and engulf apoptotic cells (efferocytosis) in the tumor microenvironment, which inhibits inflammatory responses and facilitates immune escape of tumor cells. Thus, intervention of macrophage phagocytosis by blocking anti-phagocytic signals on live tumor cells or inhibiting tumor efferocytosis presents a promising strategy for the development of cancer immunotherapies. Here, the regulation of macrophage-mediated tumor cell phagocytosis is first summarized, followed by an overview of strategies targeting macrophage phagocytosis for the development of antitumor therapies. Given the potential off-target effects associated with the administration of traditional therapeutics (for example, monoclonal antibodies, small molecule inhibitors), we highlight the opportunity for nanomedicine in macrophage phagocytosis intervention.

Keywords: TAM receptors; cancer immunotherapy; efferocytosis; innate immune checkpoints; macrophage phagocytosis; nanomedicine.

Figure 1.

Anti-phagocytic checkpoints in the tumor microenvironment. The expression of “don’t eat me” signals on tumor cells, including CD47, PD-L1, MHC-I, and CD24, protect tumor cells from phagocytic clearance by interacting with their cognate receptors on macrophages.

Figure 2.

Macrophage-mediated phagocytosis of apoptotic cells. Externalized PtdSer on apoptotic cells, as the most widely studied “eat me” signal, can be recognized by macrophages with the assistance of various receptors. Phagocytic receptors, including TIM4, BAI1, CD300b, and stabilin 2, can directly bind to PtdSer for apoptotic cell recognition. TAM receptors (Tyro3, Axl, and MerTK) and αvβ3/αvβ5 integrins, however, rely on bridging ligands (Gas6/Pros1 and MFGE8) for the recognition of externalized PtdSer.

Figure 3.

The design of the anti-SIRPα-AK750 nanoparticles for cancer therapy. A) Cancer cells use the CD47-SIRPα interaction to inhibit macrophage phagocytosis and the CSF-1R signaling further promotes the polarization of macrophages to a protumor M2 phenotype. B) Schematic demonstration of the anticancer effect of the dual-function nanoparticle anti-SIRPα-AK750. Anti-SIRPα-AK750 repolarizes macrophages to an antitumor M1 phenotype following sustained inhibition of CSF-1R signaling and improves macrophage-mediated phagocytosis of tumor cells with the blockade of CD47-SIRPα interaction. All panels adapted with permission.^[104] Copyright 2018, Springer Nature.

Figure 4.

Schematic illustration of the preparation and antitumor effect of the engineered M1 exosomes with antibodies targeting both CD47 and SIRPα. Adapted with permission.^[106] Copyright 2020, Wiley-VCH.

Figure 5.

Schematic demonstration of the in situ sprayed bioresponsive therapeutic fibrin gel containing aCD47@CaCO3 nanoparticles for the inhibition of local tumor recurrence after surgery. The aCD47@CaCO3 nanoparticles are embedded in the fibrin gel to serve as a release reservoir and a proton scavenger for regulating the acidity of the tumor microenvironment. The fibrinogen solution containing aCD47@CaCO3 nanoparticles and thrombin solution can be quickly mixed within the tumor resection cavity and gradually release the encapsulated anti-CD47 to promote macrophage phagocytosis of cancer cells. Adapted with permission.^[107] Copyright 2019, Springer Nature.

Figure 6.

The design of ROS-responsive aPD1@aCD47 protein complex and its synergistic antitumor effect by sequentially releasing anti-CD47 and anti-PD1 in the tumor microenvironment. Adapted with permission.^[109] Copyright 2019, American Chemical Society.

Figure 7.

Delivery of the plasmid DNA encoding PD-L1 trap for immune microenvironment modulation. A) Schematic illustration of the trimeric PD-L1 trap derived from the extracellular PD-L1-binding domain of PD-1. B) Fabrication of lipid-protamine-DNA nanoparticles for the delivery of PD-L1 trap plasmid. A) Adapted with permission.^[115] Copyright 2017, American Chemical Society.