Cancer cells grow wildly and malignantly due to the unlimited proliferation of tumor cells and the mitigation of their apoptosis (Xu et al., 2016). The inhibition roles of CHM on cancer cell growth have been studied broadly for many years, and active components of CHM have been applied for clinical trials (Ling et al., 2014). For instance, kaempferol was identified to repress the mitochondrial biogenesis and antagonize the activity of ERRa and ERRg to impede tumor growth (Wang et al., 2013) (Table 1). In addition, Wang et al. (2011) found that Spatholobus suberectus Dunn (SSD) also retarded cancer growth, but its inhibitory mechanism was different from those of kaempferol. SSD inhibits tumor cell growth by inducing mitochondrial apoptosis and inhibiting the cell cycle in the G2/M phase. SSD also increases the inhibition rate of docetaxel and diminishes its side effects (Table 1). Recently, we reported that ginsenosides Rg3, Rg5, Rh2, and CK downregulated the expression of cell division cycle proteins cyclinB1, CDC2, Cytc-B, CDK-4, and CDK-6 to induce tumor cell cycle arrest in the G0/G1 phase (Chen et al., 2018).

Tumor metastasis is regarded as a major obstacle to successful cancer therapy. The blockage treatments of metastasis provide more survival opportunities for cancer patients (Ma et al., 2020). Recent investigations about the regulation of tumor metastasis were involved in one family of enzymes, the matrix metalloproteinase (MMP) family, which exacerbated tumor metastasis in TME (Kessenbrock et al., 2010). Those data were consistent with our previous findings (Qu et al., 2009, 2011). Thus, the inhibition of CHM and their active ingredients on the activity of MMPs may attenuate tumor migration/metastasis. Prunella vulgaris L. (PVL) exhibited capacity to diminish the expression levels of MMP-2 and MMP-9, further reducing liver cancer metastasis (Kim et al., 2012) (Table 2). Chen et al. (2013) found that baicalein isolated from Scutellaria baicalensis Georgi (BCL) decreased the levels of MMP-2, MMP-9, and u-PA while elevating the expression of TIMP-1 and TIMP-2 to reduce the migration and metastasis of liver cancer cells through the decreased phosphorylation levels of MEK1 and ERK. In addition, the lung metastasis rate was found to be significantly decreased in the baicalein-treated nude mouse model LCID20 (Chen et al., 2013) (Table 2). As baicalein, formononetin was also found to induce the decreased levels of both MMP-2 and MMP-9 to prevent the lung metastasis of MDA-MB-231 and 4T1 breast cancer cells. However, its role is regulated through PI3K/AKT signaling pathways (Zhou et al., 2014) (Table 2). For human ovarian cancer cell lines, both crude polysaccharides isolated from Rosa roxburghii Tratt and tanshinone IIA reduced the high MMP9 expression, which was related to tumor stage and lymph node metastasis (Chen et al., 2014; Zhang et al., 2016) (Table 2).

Either cancer cells or stroma cells activate transforming growth factor-beta (TGF-β) to produce MMPs or other factors in the extracellular matrix, further facilitating the tumor metastasis (Stuelten et al., 2005). TCM herbs such as ursolic acid (UA) treatment reduces the expression levels of TGF-β1 and the phosphorylation of Smad2/3 to block Zinc Finger E-Box Binding Homeobox 1 (ZEB1), further inducing the increased levels of miR-200c to reduce the invasive potential of colon cancer cells, suggesting that UA prevented colon cancer cell invasion through the TGF-β1/ZEB1/miR-200c signaling pathway (Zhang L. et al., 2019) (Table 2). Conyza blinii saponin (CBS) isolated from Eschenbachia blinii (H.Lév.) Brouillet inhibits the activation of TGF-β signaling pathway and the phosphorylation of ERK, JNK, and p38 MAPK. CBS also reduces the expression of Nrf2 in HeLa cells, inhibits the activation of ARE, and increases the level of ROS (Peng et al., 2020) (Table 2).

Epithelial–mesenchymal transition (EMT) is also shown to promote tumor metastasis. Some CHM inhibit EMT to prevent tumor metastasis. Qingyihuaji formula (QYHJ) impaired EMT in pancreatic cancer to restrain tumor metastasis via the decreased levels of vimentin, N-cadherin, and Slug (Zhang et al., 2013) (Table 2). Therefore, CHM and their active constituents inhibited the growth, invasion, and metastasis of different types of tumor through the blockage of tumor-related signaling pathways.

Macrophages, one type of versatile immunocytes, display different phenotypes, depending on their microenvironment. Activated macrophages are classified into the M1 and M2 phenotype. In general, M1 macrophages foster inflammation response against invading pathogens and tumor cells, whereas M2 macrophages tend to exert an immune suppressive phenotype, favoring tumor progression (He et al., 2020a). Even though TAMs exhibit either polarization phenotype, they are considered as M2-like phenotype-acquired macrophages and produce epidermal growth factor (EGF) and MMPs to accelerate the migration and angiogenesis of tumor in TME (Guo et al., 2018; He et al., 2020b). Therefore, therapeutic strategies are to re-educate the M2 phenotype (pro-tumorigenesis) into antitumor M1 phenotype (anti-tumorigenesis), preventing the promotion roles of TAM in tumors (Quail and Joyce, 2013).

Dendritic cells are the principal APCs of the human body, which can efficiently ingest, process, and present antigens under physiological conditions. TME affects aggregation, maturation, and survival of DCs, and hampers the antigen presentation of DCs and sustains dysfunctional DCs to escape immune recognition, leading to the formation of tumor-associated DCs (TADCs), which exhibits a low ability to present antigen and facilitates T cells differentiating to Treg subtype, further impairing T cell-mediated antitumor activity (Giovanelli et al., 2019; Lee et al., 2020). Therefore, it is an effective way for antitumor immunotherapy to boost antigen presentation ability of DCs.

Myeloid-derived suppressor cells, as the important TIMPs, aggregate in TME and exhibit strong immunosuppressive activity to T cell antitumor response. In TME, plenty of IMCs were differentiated into large amounts of MDSCs, whereas the differentiation of MDSC into mature macrophage or DCs was prevented (Gabrilovich and Nagaraj, 2009). In the section, we discuss the functional roles of CHM on differentiation, expansion, and suppressive function of MDSCs within TME from murine tumor models, since the investigations about the regulation of CHM on tumor MDSCs are focused on murine tumor models mainly.

Myeloid-derived suppressor cells are not present in the circulation under normal physiological conditions, but these cells accumulate in the tumor-bearing mice. MDSC accumulation was downregulated by TCM herbs, such as Shen-Ling-Bai-Zhu San (SBS) formula, Shu-Gan-Jian-Pi formula (SGJP), Water extract of Pilose Antler (PA), and RSV. In the colitis-associated colorectal cancer (CaCRC) mouse model, SBS upregulates β-catenin, p53, and proliferating cell nuclear antigen (PCNA), and reduces the mortality and the number of MDSCs. It also alleviates TGF-β1-induced EMT through downregulating N-cadherin (N-cad), Vimentin, Fibronectin, and Snail, and upregulating E-cadherin (E-cad) (Lin et al., 2015) (Figure 4 and Table 4). In breast cancer mouse models, both SGJP and PA inhibit the numbers of MDSCs to increase the proportion of CD4+ T cells, CD8+ T cells, and NK cells in peripheral blood of mice, further improving the survival rates of mice and blocking tumor growth (Lu et al., 2017; Zheng et al., 2018) (Table 4). In Lewis lung cancer-bearing mice, RSV was shown to diminish the accumulation of G-MDSCs and promote M-MDSC differentiation into macrophages and the expansion of CD8+IFN-γ+ cells (Zhao Y. et al., 2018) (Table 4). Recently, Yue et al. (2018) reported that four types of TCM herbs, Andrographis paniculata (Burm.f.) Nees (AP), Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. (AS), Camellia sinensis Kuntze (CS), and Scleromitrion diffusum (Willd.) R.J. Wang (SD) reduced tumor tissue weights and tumor metastasis of both lung and liver, and decreased the numbers of both Tregs and MDSCs to coordinate the antitumor response of T cells to cancer cells, prolonging the survival period of mice in the metastatic breast cancer mouse model (Table 4). In the EL-4 thymoma mouse model, Korean red ginseng (KRG) was displayed to prevent the abnormal differentiation of IMCs into MDSCs and impair MDSC function, inducing T cell proliferation and secretion of both IL-2 and IFN-γ (Jeon et al., 2011) (Figure 4 and Table 4). In H22 hepatocellular carcinoma-bearing mice, Jianpi Huayu decoction (JHD) significantly diminishes the destruction of spleen structure and the ratios of between Treg and Th17, and increases the ratios of CTL, DC, and MDSCs in the spleen. JHD also promotes the differentiation of IMCs into macrophages and mDCs, and weakens the expression of ROS in MDSCs to impair the inhibitory effect of those MDSCs on CD4+ T cell proliferation (Xie et al., 2020) (Figure 4 and Table 4). In 4T1 breast cancer mouse model, which is a suitable experimental animal model for human mammary cancer, artemisinin (ART) significantly promotes 4T1 tumor cell apoptosis and decreases TGF-β levels and the numbers of both MDSC and Treg to inhibit tumor growth in mice (Cao Y. et al., 2019) (Figure 4 and Table 4).

The suppressive function of MDSC on T cell antitumor response has been studied broadly in our laboratory and other institutes (Qu et al., 2012; Fultang et al., 2019; Su et al., 2019). There are growing evidence that the immune-regulatory roles of CHM on the function of MDSCs become one of the major cancer immunotherapies of CHM progressively. CHM reverses the function of MDSCs through tumor-related signaling pathways such as the JAK/STATs and TGF-β/Smads pathway. Mao et al. (2018) found that, in breast cancer mouse models, Yang-He decoction (YHD) depressed the expression of iNOS, ARG-1, IL-6, TGF-β, and p-STAT3 on MDSCs and significantly increased the expression of IFN-γ and NKTs on CD4⁺T cells to shrink tumor growth (Table 4). Icariin (ICA) from Epimedium sagittatum (Siebold & Zucc.) Maxim downregulates the expression levels of IL-10, IL-6, S100A8/9, iNOS, and ROS on MDSCs to attenuate the roles of MDSCs through the inactivation of STAT3 (Zhou et al., 2011) (Table 4). In the murine sarcoma model, corosolic acid (CA) was revealed to induce the decreased expression levels of both cyclooxygenase-2 (Cox2) and CCL2 through the inactivation of Stat3 to impair the immunosuppressive activity of MDSCs (Horlad et al., 2013) (Table 4). Recently, Bao-Yuan-Jie-Du decoction (BYJD) is found to suppress the protein expression of TGF-β, Smad2, Smad3, p-Smad2/3, and Smad4 through the TGF-β/Smads signaling pathway to inhibit the recruitment of MDSCs in the lung and prolong the survival time of 4T1 tumor-bearing mice (Tian et al., 2020) (Table 4). In summary, CHM and their compounds stimulate the differentiation of MDSCs into mature myeloid cells, diminish the number and expansion of MDSCs, and restrain the suppressive function of MDSCs to block the tumor metastasis in TME.