The Role of Macrophages in Cancer Development and Therapy

Abstract

Macrophages are critical mediators of tissue homeostasis and influence various aspects of immunity. Tumor-associated macrophages are one of the main cellular components of the tumor microenvironment. Depending on their activation status, macrophages can exert a dual influence on tumorigenesis by either antagonizing the cytotoxic activity of immune cells or, less frequently, by enhancing antitumor responses. In most situations, TAMs suppress T cell recruitment and function or regulate other aspects of tumor immunity. The importance of TAMs targeting in cancer therapy is derived from the strong association between the high infiltration of TAMs in the tumor tissue with poor patient prognosis. Several macrophage-targeting approaches in anticancer therapy are developed, including TAM depletion, inhibition of new TAM differentiation, or re-education of TAM activation for cancer cell phagocytosis. In this review, we will describe the role of TAMs in tumor development, including such aspects as protumorigenic inflammation, immune suppression, neoangiogenesis, and enhancement of tissue invasion and distant metastasis. Furthermore, we will discuss therapeutic approaches that aim to deplete TAMs or, on the contrary, re-educate TAMs for cancer cell phagocytosis and antitumor immunity.

Keywords: immune suppression; immunotherapy; macrophage; tumor; tumor microenvironment; tumor-associated macrophages.

Figure 1

A spectrum of macrophage activation. The functional M1-M2 spectrum subdivisions of activated macrophages, derived from human monocytes or mouse bone marrow upon CSF-1 stimulation. Stimulation conditions are IL-4, immune complexes (Ic), IL-10, glucocorticoids (GC) with TGFβ, glucocorticoids alone, LPS, LPS and IFNγ, and IFNγ alone.

Figure 2

Mechanisms of tumorigenesis stimulation by TAMs. TAMs play an important role in the process of tumorigenesis by induction of inflammation (top left loop), stimulation of neoangiogenesis (top right loop), immune suppression (bottom left loop), and induction of metastasis (bottom right loop). The figure was created with Biorender.com.

Figure 3

Strategies to target TAMs for anticancer therapy. Two main strategies are used to target TAMs in the TME, reduction of the number of macrophages in the tumor (top panel) or re-education of macrophages (bottom panel). Several molecular targets have been discovered to apply therapies targeting TAMs (mentioned in the figure), and various therapeutics have been developed that target these molecules, including small molecule inhibitors, monoclonal antibodies, soluble ligands, bispecific fusion proteins, and antibody fragments, and nanoparticles. The figure was created with Biorender.com.