The Impact of the Tumor Microenvironment on Macrophage Polarization in Cancer Metastatic Progression

Abstract

Rather than primary solid tumors, metastasis is one of the hallmarks of most cancer deaths. Metastasis is a multistage event in which cancer cells escape from the primary tumor survive in the circulation and disseminate to distant sites. According to Stephen Paget's "Seed and Soil" hypothesis, metastatic capacity is determined not only by the internal oncogenic driving force but also by the external environment of tumor cells. Throughout the body, macrophages are required for maintaining tissue homeostasis, even in the tumor milieu. To fulfill these multiple functions, macrophages are polarized from the inflammation status (M1-like) to anti-inflammation status (M2-like) to maintain the balance between inflammation and regeneration. However, tumor cell-enforced tumor-associated macrophages (TAMs) (a high M2/M1 ratio status) are associated with poor prognosis for most solid tumors, such as ovarian cancer. In fact, clinical evidence has verified that TAMs, representing up to 50% of the tumor mass, exert both protumor and immunosuppressive effects in promoting tumor metastasis through secretion of interleukin 10 (IL10), transforming growth factor β (TGFβ), and VEGF, expression of PD-1 and consumption of arginine to inhibit T cell anti-tumor function. However, the underlying molecular mechanisms by which the tumor microenvironment favors reprogramming of macrophages to TAMs to establish a premetastatic niche remain controversial. In this review, we examine the latest investigations of TAMs during tumor development, the microenvironmental factors involved in macrophage polarization, and the mechanisms of TAM-mediated tumor metastasis. We hope to dissect the critical roles of TAMs in tumor metastasis, and the potential applications of TAM-targeted therapeutic strategies in cancer treatment are discussed.

Keywords: macrophage polarization; peritoneal metastasis; premetastatic niche; tumor microenvironment; tumor-associated macrophages.

Figure 1

Macrophage M1/M2 polarization status maintains organizational stability. IFN-γ, LPS, GMCSF are the key stimulators of classically activated macrophages (recognized as M1). During the acute inflammation phase, M1 macrophage induces inflammatory responses by expressing cell surface markers to attract immune cells and releasing inflammatory factors. On the other hand, IL4 and IL13 are inducers of alternatively activated macrophages (recognized as M2), which switch the inflammatory response to anti-inflammatory to carry out tissue remodeling function.

Figure 2

The crosstalk of tumor cells and TAMs. Tumor cells secrete different cytokines or exosomes to polarize macrophages into TAMs directly and hijacking macrophages by metabolites or limiting oxygen concentration indirectly. On the other hand, the polarized TAMs express PD-L1, SIRPα, or Siglec-10 to inhibit the anti-tumor function.

Figure 3

Co-evolution of cancer cells and TAMs in tumor progression. The early stage of the primary tumor exhibits more M1-like TAMs, T cells, and NK cells. Along with disease progression, tumor cells promote M2-TAM polarization and utilize M2-like TAMs to inhibit effector T cell or NK cell infiltration. Moreover, TAMs promote tumor spheroid formation and facilitates peritoneal metastasis. The polarized M2-like TAMs create the immunosuppressive micro-environment for facilitating metastatic tumor progression by secreting cytokines, such as VEGF, to induce angiogenesis, releasing inflammatory factors to recruit circulating monocytes to tumor mass, utilizing amino acids like arginine to inhibit T cells function, and promoting tumor spheroid formation to facilitate tumor metastasis.

Figure 4

TAM-targeted therapy in tumors. Targeting TAM strategies consists of (a) the inhibition of the recruitment of macrophages to tumor mass; (b) reprogramming TAMs into M1-like macrophages to strengthen antitumor ability (c) the activation of “phagocytic checkpoint” to restore macrophage phagocytic function; and (d) targeting cGAS-STING pathway in TAMs is a potential anti-tumor approach.