Tumor-Associated Macrophages: A Potential Target for Cancer Therapy

Abstract

Macrophages, an important class of innate immune cells that maintain body homeostasis and ward off foreign pathogens, exhibit a high degree of plasticity and play a supportive role in different tissues and organs. Thus, dysfunction of macrophages may contribute to advancement of several diseases, including cancer. Macrophages within the tumor microenvironment are known as tumor-associated macrophages (TAMs), which typically promote cancer cell initiation and proliferation, accelerate angiogenesis, and tame anti-tumor immunity to promote tumor progression and metastasis. Massive infiltration of TAMs or enrichment of TAM-related markers usually indicates cancer progression and a poor prognosis, and consequently tumor immunotherapies targeting TAMs have gained significant attention. Here, we review the interaction between TAMs and cancer cells, discuss the origin, differentiation and phenotype of TAMs, and highlight the role of TAMs in pro-cancer functions such as tumor initiation and development, invasive metastasis, and immunosuppression. Finally, we review therapies targeting TAMs, which are very promising therapeutic strategies for malignant tumors.

Keywords: cancer; cancer immunotherapy; macrophages; tumor microenvironment; tumor-associated macrophages.

Figure 1

Origin and Heterogeneity of TAMs. Macrophages in tumors actually have at least three sources, including bone marrow, fetal liver and embryonic yolk sac. Bone-marrow-derived macrophages (BMDMs) develop from hematopoietic stem cells in the bone marrow, while tissue-resident macrophages (TRMs) develop from erythro-myeloid progenitors in the fetal liver or embryonic yolk sac. TAMs can differentiate into various phenotypes upon stimulation by different signals in the tumor microenvironment, and the protumor and antitumor phenotypes are the two extremes of the spectrum.

Figure 2

TAMs are involved in almost all aspects of tumor cell biology through various mechanisms, such as tumor initiation, proliferation, angiogenesis, metastasis, immunosuppression, resistance to therapy, and cancer stem cell maintenance.

Figure 3

Treatment Strategies targeting TAMs. (1) Inhibition of TAM recruitment by blocking the CCL2/CCR2 or CXCL2/CXCR4 axis. (2) Depletion of TAMs by blocking the CSF-1/CSF-1R axis or using compounds such as bisphosphonates or trabectedin. (3) Reprogramming of TAMs to activate their anti-cancer function by CD47/STRPα pathway inhibitors, MHC I/LILRB1 pathway inhibitors, CD40 agonists, toll-like receptors agonists, Glufosinate, PI3Kγ inhibitors, or HDAC inhibitors.