Macrophages are white blood cells that exist in tissue. It is generally believed that macrophages are derived from monocytes, while monocytes are derived from the granulocyte-macrophage colony (GM-CFUc) forming unit in bone marrow. Monocytes migrate from blood to different tissues and form groups of cells with different functions, such as “inflammatory” monocytes and “resident” monocytes distinguished by the expression of cell surface marker CX3CR1 (21). Inflammatory monocytes have a short half-life and can differentiate into inflammatory macrophages and dendritic cells. Inflammatory monocytes may also be one of the sources of resident monocytes. Resident macrophages are usually produced by resident monocytes and sometimes by inflammatory monocytes. Resident macrophages and Foxp3⁺T cells play an important role in maintaining the stability of intestinal environment through the mechanism of IL-10 and TGF-β dependence. When intestinal inflammation occurs, inflammatory monocytes migrate to the intestinal tract and differentiate into dendritic cells and inflammatory macrophages, which can produce a variety of cytokines involved in inflammatory response (22). Inflammatory macrophages are usually activated as M1 phenotype, while resident macrophages are usually activated as M2 phenotype. This process, which is affected by a variety of complex factors, is known as polarization. The polarization of macrophages is dynamic and could be reversed under certain conditions. The polarized macrophages mainly include M1 activated by classical pathway and M2 activated by alternative pathway (23). M2 can be divided into four subtypes in response to various stimuli: M2a (24), M2b (25), M2c (26) and M2d (27).

Inflammatory cytokines, such as IFN- γ, TNF-α, and the microbial product LPS stimulate M1 polarization of macrophages (28). TLR2, TLR4, CD80, CD86, and CCR7 are among the surface receptors expressed by M1. And M1 secretes a variety of inflammatory cytokines and chemokines, including TNF-α, IL-6, IL-1, IL-12, ROS, CXCL9, CXCL10, CXCL11, CCL2, CCL3, CCL4 and CCL5 (29). Polarized M1 macrophages have increased antigen presentation ability (30). As a result, M1 shows strong inflammation, antibacterial and anti-tumor performance. Th-2 cytokines IL-4, IL-10 and IL-13 can stimulate M2 polarization of macrophages (31). Dectin-1, mannose receptor, scavenger receptor A/B, DC-SIGN (CD209) and CD163, CCR2, CXCR1, and CXCR2 expression in M2 macrophages. As the main member of tumor-associated macrophages TAMs, M2 has strong phagocytic ability, removes fragments and apoptotic cells, promote tissue repair, angiogenesis, suppresses immunity, and promotes tumor progression and metastasis (32).

The immune state of the body is maintained by the coordination of a variety of immune cells. The interaction between macrophages and other immune cells is complex and diverse, which can regulate the direction and intensity of immune response through a variety of ways and mechanisms, thus having different effects on the body.

Skin and mucosa are the first line of immune defense of the body. In intestinal mucosa, macrophages and dendritic cells play an innate immune role, while B cells and T cells participate in adaptive immune response. Macrophages are important cells in chronic inflammation and the pathological processes. And macrophage infiltration is a sign of chronic inflammation. The polarization of macrophages is associated with some autoimmune diseases, such as UC (45) and systemic lupus erythematosus (46). Under physiological conditions, macrophages in the intestine phagocytize microorganisms and present antigens to activate T cells. Excessive activation of macrophages transforms physiological inflammation into pathological damage of intestinal mucosa. The number of macrophages increased significantly in active ulcerative colitis, suggesting that macrophages were involved in the occurrence and development of UC (47). And during the active phase of UC, most of the macrophages in the lamina propria of the intestinal wall are M1 phenotype. M1 breaks down tight junction proteins, destroys the epithelial barrier, induces apoptosis of epithelial cells, and leads to excessive inflammation (48). M1 plays a major role in intestinal inflammation, while M2 plays an antagonistic role which eliminates inflammation and promotes tissue healing. Previous studies have confirmed that increasing the proportion of M2 could reduce the symptoms of colitis in mice (49).

A variety of inflammatory cytokines secreted by macrophages play an important role in UC. IL-6 is an important mediator in inflammatory response, which directly participates in inflammatory response and corresponding injury process. IL-6 increases the permeability of epithelial cells, which promotes the infiltration of macrophages and aggravate the development of ulcerative colitis. Previous studies have shown that the level of IL-6 is positively correlated with the severity of intestinal inflammation (50). IL-18 is also highly expressed in serum and colon tissues of patients with ulcerative colitis. The application of IL-18 inhibitor relieves the symptoms of mouse colitis model and reduce the expression of many inflammatory factors (51). TNF-α regulates the NF-κB pathway by promoting IκBα degradation, NF-κB p65 phosphorylation and NF-κB nuclear transfer, which aggravates the injury of ulcerative colitis (52). Infliximab has been used as a TNF-α antagonist in the treatment of ulcerative colitis (53).

These cytokines not only play a role in the inflammatory response, but also participate in the tumorigenesis and progression of tumors. TNF- α is a kind of inflammatory cytokine with strong anti-tumor effect (54). Many kinds of immune cells, including macrophages, can produce TNF- α. It has been shown to promote tumor growth in chronic inflammatory diseases, although TNF- α has anti-tumor property. In chronic inflammation, by production of RONS, TNF- α promotes DNA damage caused by oxidative stress and promotes the tumorigenesis of CAC (55). And targeting TNF- α may prevent or reduce the tumorigenesis of CAC (56). Similarly, IL-6 can also promote early CAC tumorigenesis by inducing oxidative stress (57).

Interestingly, although TNF- α has anti-tumor effect, even some studies have shown that TNF- α can promote tumor cell apoptosis and inhibit tumor liver metastasis in colorectal cancer (58). However, more studies have found that TNF- α plays an important role in tumor progression. By stimulating epithelial-mesenchymal transformation, TNF- α can enhance the ability of invasion and metastasis of colon cancer cells (59). And TNF- α can promote angiogenesis by inducing human fibroblasts to secrete VEGF (60). TNF- α can also promote tumor lymphangiogenesis and lymphatic metastasis (61). In addition, TNF- α promote the progression and metastasis of CRC through NF- κ B pathway and induction of MACC1 (62, 63). By blocking TNF- α, the promotion of TNF- α on tumor can be reduced (64, 65).

Inflammation is an important cause of carcinogenesis of UC. Macrophage infiltration is one of the characteristics of inflammation in UC. A large number of infiltrating macrophages aggravate the mucosal damage caused by inflammation and promote the transformation from inflammation to tumor. The infiltration of macrophages and the release of pro-inflammatory factors promote the carcinogenesis of epithelial cells.

CCL2 and CX3CL1 are important cytokines that induce macrophage infiltration. By promoting the expression of these cytokines, macrophage infiltration is enhanced and the occurrence and development of CAC is promoted. MUC1 is a kind of cell surface mucin which exists in intestinal epithelial cells and some leukocytes. MUC1 promotes the expression of CCL2 and mediates the recruitment and activation of macrophages. Activated macrophages secrete IL-6 and promote the occurrence and development of CAC through IL-6/STAT3 pathway (68). Glucocorticoid is a drug for the treatment of active UC. In an acute experimental UC mouse study, it was found that glucocorticoid increased the expression of CCL2 and CX3CL1, promoted macrophage infiltration and promoted the occurrence of UC and CAC by targeting mTOR signal of intestinal epithelial cells (69). Corticotrophin-releasing hormone receptor (CRHR1) belongs to the CRH family and is highly expressed in inflammatory tissues adjacent to CAC tumor tissue. CRHR1 promotes the recruitment of macrophages, secretes more inflammatory factors such as IL-1b, IL-6 and TNF- α, and promotes the early occurrence of CAC (70).

And inhibition of macrophage infiltration reduces the occurrence and development of inflammation and CAC. By inhibiting the expression of CCL2, GDC-0575, a CHK1 inhibitor, reduces macrophage infiltration in the mouse colon, which may inhibit the occurrence of CAC and colitis (71). Suppressor of AP‐1 (SAR1), a tumor suppressor, down-regulates the expression of p-STAT1 and STAT1 in CAC cells, inhibits the activation of MCP-1/CCR2 axis, reduces macrophage infiltration, which may inhibit the tumorigenesis of CAC (72). Serum amyloid A (SAA) is an evolutionarily conserved protein family associated with inflammation. It was found that in the CAC mouse model, SAA deficient mice showed a decrease in macrophage infiltration, which may inhibits tumorigenesis of CAC (73). Nerve injury inducer protein 1 (ninjurin1) is a homogenous cell surface adhesion molecule, which plays an important role in cell migration. Overexpression of Ninjurin1 in macrophages weakens the infiltration of macrophages by targeting FAK signaling pathway, thus may inhibiting the tumor progression of CAC (74). Diphenyleneiodonium (DPI) is an inhibitor of NADPH oxidase, which inhibits a variety of inflammatory responses. Low-dose DPI inhibits macrophage infiltration and migration, reduce the production of pro-inflammatory cytokines such as TNF- α and IL-6, reduce inflammatory response and may inhibit tumorigenesis (75). Estrogen receptor β (Erβ) reduce the occurrence and development of tumor by reducing macrophage infiltration and reducing the production of TNF-α (76). As a non-coding RNA, miRNA cannot encode proteins, but it can still exert its biological functions in a variety of physiological or pathological processes. A large number of previous studies have confirmed that miRNA plays an important role in inflammation and tumor (77, 78). Abdullah et al. found that overexpression of miR-132 inhibits macrophage infiltration and the production of proinflammatory cytokines, which may inhibit CAC (79).

These factors that affect macrophage infiltration are quite pleiotropic and have numerous downstream targeting effects, so the impact on CAC may not be direct, and may not all be caused by macrophage infiltration. And the effect of macrophage infiltration on CAC mainly occurred in the early stage. The underlying mechanism may be the large amount of macrophage infiltration leads to more severe intestinal inflammation. A large number of cytokines produced by macrophages promote DNA damage and promote the process of inflammation-dysplasia-tumor. The regulation of intestinal macrophage infiltration affects the tumorigenesis of CAC ( Figure 1 ). Therefore, early inhibition of macrophage infiltration may be of significance to not only reduce the inflammation of ulcerative colitis but also prevent the occurrence of CAC.

Macrophages express different phenotypes under the influence of different environments, which is called macrophage polarization (80). The polarized macrophages mainly include M1 activated by classical pathway and M2 activated by alternative pathway. M1 and M2 have different functions. M1 secretes inflammatory cytokines and enhances the inflammatory response, but it has the anticancer effect of enhancing tumor immunity in tumor tissues. M2 promotes tissue repair and has anti-inflammatory effect, but it is considered to inhibit tumor immunity in tumor tissue. This means that macrophage polarization can not only affect the occurrence of CAC by regulating inflammation, but also directly affect CAC by regulating tumor microenvironment.

Excessive M1 polarization aggravates the inflammatory symptoms of the UC, promotes mutation involvement and provides an inflammatory environment suitable for tumorigenesis. M2 antagonize the pro-inflammatory effect of M1 and inhibit tumorigenesis. Low-dose DPI inhibited the classical activation pathway of macrophages and the level of M1 by down-regulating the pathways of STAT3, NF-κB and ERK, and inhibited the tumorigenesis of CAC in the early stage (75). MiR-146b targets MyD88 and IRAK1, regulates TLR4 pathway, inhibits M1 activation, and then reduces inflammation and inhibits the tumorigenesis of CAC (81). In the early stage of CAC, xanthine oxidoreductase (XOR) mediated M1 macrophage polarization, which promoted the tumorigenesis of CAC (82). In macrophage, Fibrinogen-like protein 2 (Fgl2) deficiency promotes M1 polarization and inhibit M2 polarization, which promote the tumorigenesis of CAC (83).

However, inflammation is not the only factor affecting the tumorigenesis of UC. M2 macrophages in tumor microenvironment also have the effect of pro-tumor. In myofibroblasts, MyD88 secretes OPN through TLR pathway, binds to CD44 and αvβ3 on macrophages, promotes M2 polarization through STAT3 and PPARγ pathway, which promotes the tumorigenesis of CAC (84). And a study found that the loss of SLC7A2 enhanced M2 polarization to promote the tumorigenesis of CAC (85).

After tumor formation, M1 plays an anti-tumor role through direct tumoricidal mechanisms or by promoting CD8 cytotoxic T cell and NK cell killing of tumor cells in later phases of CAC progression. M2 promotes tumor immune escape and enhanced tumor progression, especially invasion and metastasis. In a study on vitexin in CAC mice, vitexin inhibited M1 polarization in inflammatory tissue, but promoted M1 polarization in tumor tissue, which reduces tumorigenesis, inhibited tumor progression, and reduced tumor load (86). Transient receptor potential vanilloid 1 (TRPV1) is an ion channel expressed in a variety of immune cells. In the early stage of CAC, TRPV1 directly stimulates M1 polarization and promotes tumorigenesis. After that, TRPV1 regulates the Calcineurin/NFATc2 pathway to increase the phenotype of Th2, enhance M2 polarization and promote tumor progression (87). IL-28B inhibits M2 polarization of macrophages through STAT3 and JNK signaling pathways, which reduces the expression of M2 cytokines Arg-1 and TGF-β, to inhibit the tumor progression of CAC (88). Hematopoietic cell kinase (HCK) is one of nine non-receptor tyrosine kinases in the SRC family, which has the function of regulating innate immunity. HCK promotes M2 polarization which promotes the tumor progression of CAC (89) ( Figure 2 ).

Tumor immunity is an important factor affecting tumor progression. The main reason for the effect of macrophage polarization on CAC is that polarized M1 and M2 play different functions in tumor immunity.

M1 produces ROS, which can directly kill tumor cells and inhibit tumor growth. M1 macrophages can produce a series of pro-inflammatory cytokines, including TNF- α, IL-1 β, IL-6, IL-12. These cytokines can stimulate the activity of immune cells such as NK cells and CD8+T cells and enhance their ability to attack tumor cells (90). In addition, M1 macrophages can activate tumor-specific T cells through antigen presentation and mature DC cells, thus promoting anti-tumor immune response (91). Recent studies have shown that M1 macrophages can also enhance anti-tumor immune response by inhibiting immunosuppressive cells in tumor microenvironment, including Tregs and MDSCs (92).M2 cells play an important role in different stages of tumor progression. In the early stage of tumor, M2 macrophages are mainly involved in tumor growth and angiogenesis. They secrete a variety of growth factors and cytokines, including VEGF, TGF- β, EGF, which promote tumor cell proliferation and neovascularization. In the middle stage of the tumor, M2 macrophages mainly play an immunosuppressive role. They can inhibit the activity of tumor immune cells and reduce the immune recognition and killing of tumor cells by secreting a variety of cytokines and surface molecules, including IL-10, TGF- β, PD-L1. In the late stage of tumor, M2 macrophages are mainly involved in tumor invasion and metastasis. By secreting a variety of proteases and lysosomal enzymes, they can promote tumor cell infiltration and invasion of surrounding tissues, and promote tumor cell metastasis and distant metastasis (36, 93–95). In general, M2 macrophages have complex mechanisms in the process of tumor growth and development, which can not only promote tumor growth and angiogenesis, but also inhibit the activity of tumor immune cells and promote tumor invasion and metastasis. Tumor cells also produce cytokines that affect the differentiation and function of immune cells. Some studies have shown that G-CSF released by tumor cells can activate MDSCs, thus forming an immune microenvironment suitable for tumor progression. In mechanism, MDSCs expresses high levels of inhibitory receptors and ligands, such as PD-L1, B7-H1 and CTLA-4, which can bind to T cell activation signal molecules (such as CD28), thus inhibiting T cell activation and proliferation. MDSCs can produce a variety of immunosuppressive molecules, including ROS, TGF- β, IL-10. These molecules can directly or indirectly inhibit the function and proliferation of T cells. MDSCs can promote T cell apoptosis through a variety of mechanisms, including secreting apoptosis-inducing molecules, expressing apoptosis-inducing receptors, inhibiting survival signals (96–98). These production of factors by MDSC and M2 macrophages provide a productive microenvironment tumor invasion and metastasis during tumor progression to malignant carcinoma stage tumors, including CAC.

In addition to infiltration of a large number of macrophage and break of the balance of macrophage polarization, macrophages also affect CAC through some other mechanisms such as regulating the secretion of inflammatory cytokines or tumor-promoting factors and targeting NF-κB pathway in macrophages.

Pou3f1 is a member of POU family and participates in cell apoptosis and immune response (99, 100). Nuclear factor of activated T cell 3 (Nfatc3) targets Pou3f1 to increase its expression, while Pou3f1 can promote inflammation in macrophages. Knockout of Pou3f1 decreased the levels of pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α, and inhibited the tumorigenesis of CAC (101). G protein-coupled receptor 35 (GPR35) is a soliton G protein-coupled receptor that interacts with sodium-potassium pumps. In macrophages, GPR35 promotes macrophages to release angiogenic factors and promote angiogenesis and tumor metastasis through the activation of Na/k-ATPase and non-receptor tyrosine kinase SRC (102). Dana et al. found that in macrophages, EGFR signal activates M2 polarization through STAT6, which promotes angiogenesis and CAC progression. Interestingly, in this study, M1 polarization is also activated by EGFR signals via NF-κB. The promotion of angiogenesis and tumor metastasis is due to the joint action of M1 and M2 to produce angiogenic factors CXCL1 and VEGF (103). Macrophage scavenger receptor A1 (SR-A1) is a pattern recognition receptor, which is mainly expressed in macrophages. In macrophages, SR-A1 inhibits the classical and non-classical activation of NF-κB signal through TRAF6 and TRAF3, respectively, thus inhibiting the occurrence of colitis and CAC (104). Elongation factor Tu GTP binding domain containing 2 (EFTUD2) is a mRNA splicing protein that could promote the occurrence of CAC by regulating the inflammatory response of macrophages. In macrophages, EFTUD2 deletion reduces the secretion of inflammatory factors and inhibits the occurrence of CAC by inhibiting the activation of TLR4-NF-κB pathway (105). MiRNA26a is overexpressed in macrophages, targeting IL-6, TLR3 and PKCσ, inhibiting the activation of NF-κB/STAT3 pathway and inhibiting the occurrence and development of CAC (106). M1 promotes the expression of TNF-related apoptosis-inducing ligands (TRAIL) in adipose tissue-derived stem cells (ASCs), while ASCs induce apoptosis of CD133+ tumor cells and reduce the number of M2 through TRAIL, which inhibits the progress of CAC (107).

The discovery of these mechanisms not only gives us a deep understanding of the role of macrophages in CAC, but also provides a new direction for the treatment of CAC by targeting these molecular pathways. At present, some potential drugs for the treatment of CAC, especially traditional Chinese medicine, play a role by affecting macrophage infiltration or polarization. Some drugs that directly target these molecular pathways are highly anticipated.