Targeted consumption or regulation of TAMs has become a potential cancer treatment strategy (19), such as activating TAMs towards M1-type polarization, suppressing M2-type polarization, and inducing M2 polarizing to M1. Numerous Chinese medicine compounds have been reported to exert inhibitory effects on tumor growth and metastasis through targeting macrophages ( Figure 1 ). Th1 cytokines IFN-γ are conducive to M1 activation in the TME (20). Modified Si-Jun-Zi Decoction stimulated the secretion of GM-CSF, IFN-γ, IL-1α and IL-3, increased the number of macrophages, thus activating the innate immune system to remove colorectal cancer (CRC) cells (21). The elevated expression of phenotypic marker CD86 and CD40 stand for the activation of M1 macrophages to some extent. Ma et al. observed that Haimufang (HMF) decoction enhanced the generation of nitric oxide (NO) and reactive oxygen species (ROS), the secretion of cytokines TNF-α, IL-1β, IL-12 p70, and IL-6, and the expression of M1 marker CD40 and CD86, with time- and dose-dependent manners in RAW264.7 cells, but had no discernible impact on M2 phenotypic marker CD206. As a result, HMF promoted the M1 polarization and enhanced the phagocytosis ability (22). In hepatocellular carcinoma (HCC), Yang et al. reported that Compound kushen injection (CKI) facilitated the activation of macrophages by stimulating TNF receptor superfamily member 1 (TNFR1)-mediated NF-κB and p38 MAPK signaling pathways, thereby accelerating M1 polarization and alleviating TAMs-mediated immunosuppression (23). Yu-ping-feng (YPF) has usually been prescribed to enhance human immunity, which was reported to up-regulate the secretion of IL-1β and IL-12, the level of iNOS as well as the phosphorylation and activation of signal transducers and activators of transcription 1 (STAT1) in RAW264.7 cells to propel the M1 polarization and enhance M1-induced CD4⁺T cell activation and Lewis lung cancer (LLC) lysis (24). Furthermore, Chinese medicine compounds could restrain the function of M2 and facilitate the conversion of M2 to M1. XIAOPI (XP) formula remarkably prevented the promoting effect of TAMs on the proliferation and self-renewal activity of breast cancer cell lines (MDA-MB-231 and 4T1) in a co-culture system, and reversed the TAMs-mediated C-X-C Motif Chemokine Ligand 1 (CXCL1) secretion and β-catenin signal, thus attenuating the self-renewal activity and chemotherapy resistance of breast cancer stem cells (CSCs). Moreover, XP weakened the polarization of M2 by down-regulating the expression of CD163, CD206 and Arg1 as well as the transcriptional activity of CXCL1 in a dose-dependent manner (25). C-C Motif Chemokine Ligand-2 (CCL2) refers to an important chemokine for monocyte/macrophage chemotaxis (26). Chen et al. reported that CCL2 boosted the number of macrophages in the liver and induced M2 polarization, which could be prevented by Dahuang Zhechong Pills (DZP) through the suppressed secretion of CCL2 and its receptor CCR2, along with the low level of F4/80, TGF-β1 and FN to attenuate hepatic fibrotic status. DZP also reversed tumor-mediated M2 polarization of macrophages to reshape the immunosuppressive TME and inhibit the liver metastasis of CRC (27). Jianpi Yangzheng (JPYZ), the ingredients for invigorating qi and spleen of Jianpi Yangzheng Xiaozheng decoction, can promote the transformation of M2 to M1 with the elevation of CD86 and reduction of CD206 and CD163. The mRNA levels of M1-related genes (IL-1β, IL-12 and TNF-α) were enhanced by JPYZ while those of M2-related genes (Arg-1, Fizzl and Yml) were attenuated (28). Consequently, Chinese medicine compounds indeed regulate the activation and differentiation of TAMs to exert anti-tumor activity ( Table 1 ).

Chinese medicine compounds could enhance the maturation and antigen presentation ability of DCs to induce the activation of naïve T lymphocytes and participate in the regulation of T cell differentiation ( Table 1 ). IL-12 is closely involved in the antigen presentation function of DCs (41). Zhao et al. optimized a new traditional Chinese medicine formula Yangyin Wenyang (YYWY) on the basis of Jinfukang. YYWY intervention drove the impregnation of DCs, CD4⁺ and CD8⁺ T cells in LLC tissues, and raised the mRNA levels of IFN-γ, IL-1β, TNF-α and IL-12. In addition, YYWY stimulated MAPK and NF-κB signaling pathways in bone marrow dendritic cells (BMDCs) to accelerate the maturation of DCs and the proliferation and differentiation of T cells together (29). TSLP, an immune-related factor, can activate DCs and involve in T cell differentiation, which raises the expression of Th2-polarizing molecule CD252 (OX40L), and induces Th2 response (42). Yao et al. reported that YPF reduced the expression of TSLP and OX40L to induce the maturation of DCs and the expression of CD80, CD86, MHC-II as well as IL-12 (12). Furthermore, DCs combine with tumor cells to form fusion cells (FCs), which play an inhibitory role in tumor development. Yang et al. found that fusion cells of dendritic colon cancer stem cells (DC-cCSC FCs) facilitated the proliferation of cytokines induce killer (CIK) cells. The cytotoxicity of DC-cCSC FCs and CIK cells against cCSCs was further improved by IL-12 and could be enhanced by the Chinese medicine CKI (30). In summary, Chinese medicine compounds are capable to activate DCs. Although some studies have proven that Chinese medicine compounds elevate the function of NK cells in the TME by promoting the secretion of IL-12 ( Figure 1 ), more researches about the mechanisms are demanded.

Recently, the anti-tumor activity of exogenously activated and amplified NK cells has been proved in clinical (43). Some studies have shown that activating NK cells may be an effective approach for Chinese medicine compounds to suppress the advance of tumors ( Table 1 ). For example, Luo et al. confirmed that YPF propelled the infiltration, proliferation, and killing activity of NK cells in tumor tissues to prolong the survival of LLC tumor-bearing mice. Elimination of NK cells could remarkably reverse the inhibitory effect of YPF on lung cancer, indicating that NK cells were the potential target cells for YPF-mediated lung cancer treatment (31). Additionally, Que et al. found that Jinfukang was conducive to the secretion of C-X3-C Motif Chemokine Ligand 1 (CX3CL1) in circulating tumor cells (CTCs) and the recruitment of CTCs to NK cells. Meanwhile, Jinfukang significantly accelerated NK cells-mediated CTCs apoptosis and prevented lung cancer metastasis through activating Fas/FasL signaling pathway, manifested as the up-regulated FasL and secretion of TNF-α in NK cells (32). In addition, Tien-Hsien liquid (THL) accelerated the secretion of immune factors including IFN-γ, IL-2 and TNF-α to augment the cytotoxicity of NK cells and CTLs and mitigate the tumor development (33). Finally, Li et al. reported a new traditional Chinese medicine compound anti-cancer No.1 (ACNO) which could dose-dependently enhance the cytotoxicity of NK cells by up-regulating the secretion of IL-2, IL-12, and INF-γ (34) ( Figure 1 ). In brief, Chinese medicine compounds can interfere with tumor growth by the way of enhancing the killing activity of NK cells.

Researches have suggested that Chinese medicine compounds abated the immunosuppression in the TME by facilitating the apoptosis and differentiation of MDSCs to enhance immune response ( Table 1 ). Mao et al. observed that Yanghe Decoction (YHD) had immunomodulatory effects on 4T1 breast tumors, not only boosting the amount of NKT and CD4⁺ T cells as well as the secretion of IFN-γ and p-STAT1, but also attenuating the recruitment of MDSCs through JAK/STAT3 signaling pathway (35). YPF suppressed the mRNA levels of immunosuppressive genes in MDSCs, including Arg-1, iNOS and STAT3, and decreased the levels of p-Akt, p-MEK, p-ERK and p-STAT3 to prevent MDSCs augment and induce their apoptosis, which further modulated the proportion of T cell subsets by increasing CD4⁺/CD8⁺ T lymphocytes and decreasing Treg proportion, thus reshaping the immune TME and preventing the lung cancer progression (36). Moreover, Xie et al. proved that Jianpi Huayu Decoction (JHD) attenuated the expression of IL-10 and TGF-β in tumor tissues and accelerated the differentiation of MDSCs into macrophages and DCs. JHD decreased the content of ROS in MDSCs, inhibited CD4⁺ T cells proliferation and the percentages of Th17 and Treg, but elevated the proportion of CTLs and DCs to relieve the MDSCs-mediated immunosuppressive state in HCC (37). Another research reported that Baoyuan Jiedu decoction (BYJD), a traditional Chinese medicine formula composed of Astragalus, Ginseng, Aconite root, Honeysuckle, Angelica, and Licorice, inhibited the TGF-β/CCL9 signaling pathway and reduced the number of MDSCs in peripheral blood and spleen of breast cancer (4T1)-bearing mice. Furthermore, BYJD blocked the recruitment of MDSCs in lung, the metastatic organ of breast cancer, thereby improving the pre-metastatic niche (PMN) and prolonging the survival of tumor-bearing mice (38). Xu et al. found that the medium dose of Ze-Qi-Tang (ZQT) had the strongest anti-tumor activity. In lung carcinoma in situ, ZQT could eliminate MDSCs in a dose-dependent manner, reduce the recruitment of MDSCs, and enhance the infiltration of T cells to reverse MDSCs-mediated immunosuppression. Thoroughly discovered that ZQT suppressed the level of STAT3, p-STAT3 and anti-apoptotic protein Bcl-2, increased the expression of pro-apoptotic protein Bax, cleaved caspase-3 and PARP to induce the apoptosis of G-MDSCs in lung carcinoma in situ. However, after G-MDSCs were completely depleted, the cytotoxicity of CD8⁺ T cells and the inhibitory effect of MDSCs had no significant difference between ZQT group and the control group, suggesting that the anti-tumor activity of ZQT was achieved by targeting G-MDSCs subset (39). Chinese medicine compounds also could decline the generation of MDSCs. Shuangshen granules restrained the expression of mTOR, S6K1 and Myc to block the differentiation of bone marrow cells (BMCs) into MDSCs in a dose-dependent manner, thus preventing lung metastasis (40). XP impaired the activation of hematopoietic stem-progenitor cells (HSPCs) as well as the differentiation of HSPCs into MDSCs through TAMs/CXCL1 signaling pathway to inhibit lung metastasis of breast cancer (25). Therefore, it may be a promising therapeutic way for Chinese medicine compounds to improve TME through targeting MDSCs ( Figure 1 ).

Some Chinese medicine compounds are capable of exerting anti-tumor effects through facilitating CD4⁺T lymphocytes differentiate to Th1 and attenuating Th2 response ( Table 2 ). The activation and differentiation of CD4⁺ T lymphocytes tend to be affected by APCs, such as macrophages and DCs. YPF enhanced the antigen presentation ability of macrophages by up-regulating the level of MHC II, thereby activating the LLC cell lysis mediated by CD4⁺ T cells. Meanwhile, YPF enhanced the secretion of Th1 cytokines (IL-2, IL-12) but repressed the level of Th2 cytokines (TGF-β, IL-4) (24). In addition, in H-22 tumor-bearing mice, YPF elevated the ratio of Th1/Th2 (IFN-γ/IL-4) through mature DCs, thus ameliorating Th2-biased immune state (12). Similarly, YYWY exerted the anti-tumor effect by inducing DCs mature, which subsequently activated CD4⁺ T lymphocytes and enhanced Th1 function (29). Chen et al. found that in CT26 tumor-bearing mice, Quxie capsule (QX) intervention boosted the expression of Foxo1 and T-bet, along with the augment of Th1 and Th1/Th2, to propel the immune response in TME (44). Th17 has been considered as a potential target for tumor treatment in several studies. Deng et al. confirmed that Th17 was conducive to the occurrence of Ulcerative Colitis-Related Colorectal Cancer (UCRCC), however, Compound Sophorae Decoction (CSD) remarkably reversed the increasing number of Th17 and the secretion of IL-17 to relieve inflammation in UCRCC (45). Chuang et al. reported that in the co-culture system of spleen cells and LLC cells, JC-001 enhanced Th1 function and suppressed Th17 function by abating the secretion of TGF-β and IL-17A to prevent tumor progression (46). In liver cancer, JC-001 had the same effects on Th1 and Th17 function, thereby alleviating Treg-mediated immunosuppression (47). Taken together, Chinese medicine compounds control tumor growth by modulating the differentiation of CD4⁺ T cells, enhancing Th1 immune response as well as restraining the function of Th2 and Th17 ( Figure 1 ).

Restoring CD8⁺ T lymphocytes function has always been regarded as an effective method to facilitate tumor immunity (16). Some studies have demonstrated that Chinese medicine compounds lead to the augment of CD8⁺ T lymphocytes in tumor tissues (29, 33, 36). In addition, Chinese medicine compounds bring vital impacts on the activity and exhaustion of CD8⁺ T cells ( Table 2 ). CKI combined with sorafenib dramatically suppressed function-inhibitory receptors in CD8⁺ T cells, including lymphocyte-activation gene 3 (Lag-3), programmed cell death protein 1 (PD-1), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), and T-cell immunoglobulin and mucin-domain containing-3 (Tim-3) to reduce the depletion of CD8⁺ T cell. At the same time, the combination therapy strengthened the cytotoxicity of CD8⁺ T cells by accelerating the production of TNF-α, Perforin, IFN-γ and Granzyme-B. When CD8⁺ T lymphocytes were blocked, the anti-tumor activity of combination therapy disappeared, suggesting that CD8⁺ T cells were necessary for CKI-mediated HCC treatment (23). Lu et al. reported that, in depression breast cancer mice, Shugan Jianpi formula combined with chemotherapy drug gemcitabine (GEM) effectively repressed the apoptosis of CD8⁺ T cells and significantly reduced MDSCs to enhance the immune surveillance, thereby preventing the progress of breast cancer (48). It has been shown that Xiao-Ai-Ping, an adjuvant injection for tumor therapy, propelled the infiltration and function of CD8⁺ T cells in the TME of LLC, mainly manifested as the increase in Perforin, IFN-γ and Granzyme-B (49). At last, JC-001 drove the generation of CD8⁺ T cells in LLC1 tumor and the secretion of IL-12 p70 and IFN-γ to sensitize LLC1 tumor to chemotherapeutic drug cisplatin (CDDP) (46). Jurkat T cell line, a kind of CTLs, has been reported to resist tumor immune escape (55). Du et al. observed that Shenqi Fuzheng Injection (SFI) down-regulated the immunosuppressive cytokines IL-10, TGF-β and VEGF in A375 cells in a concentration-dependent manner. Also, SFI enhanced the cytotoxic and migratory activities of Jurkat T cells in A375 melanoma to reprogram the melanoma microenvironment (50), which demonstrated that CTLs can mediate the anti-tumor effects of Chinese medicine compounds. In conclusion, the restoration and enhancement of the activity of CD8⁺ T cells are effective ways for Chinese medicine compounds to prevent cancer from deteriorating ( Figure 1 ).

Previous researches have shown the potential therapeutic effects of targeting Foxp3⁺ Tregs for cancer treatment (56). Guo et al. reported that Feiyanning Decoction significantly attenuated the amount of CD4⁺CD25⁺ regulatory T cells in spleen, thymus and tumor tissues in LLC-bearing mice. It decreased the mRNA level of Foxp3, enhanced tumor immune response, and slowed down the progression of lung cancer (51). Yi-Yi-Fu-Zi-Bai-Jiang-San (YYFZBJS), a classical Chinese medicine formula for gastrointestinal diseases, suppressed the number of CD4⁺CD25⁺ Foxp3⁺ T cells. Although YYFZBJS did not directly affect CRC cells, it was able to down-regulate the proliferation of MC-38 cells through Enterotoxigenic Bacteroides fragilis (ETBF)-primed Tregs and preventing the advance of colon cancer (52). Moreover, Xihuang (XH) Pill reduced the proliferation of Tregs in the TME of breast cancer and induced the apoptosis of Tregs by suppressing PI3K/Akt/AP-1 signaling pathway, thus reversing the immune escape to attenuate the tumor growth (53). The imbalance of Th17/Treg often occurs in autoimmune diseases and inflammation (57), which could be effectively ameliorated by Chinese medicine compounds. CSD restored the balance of Th17/Treg by decreasing the proportion of Th17, Treg and the related inflammatory factors to improve immune function (58). Inflammation is often closely associated with the advance of cancer, thereby adjusting Th17/Treg balance in cancer may be helpful to relieve tumor-mediated immunosuppression. On the one hand, QX down-regulated Foxo1-mediated Foxp3, reduced Tregs and recovered the balance of Th17/Treg, thus playing a therapeutic role in CRC (44). On the other hand, Liu et al. found that Fuzheng Fangai combined with cyclophosphamide (CTX) effectively decreased the proportion of Th17 and Treg in spleen and tumor tissues of LLC tumor-bearing mice and restored the ratio of Th17/Treg. Meanwhile, the secretion of IL-17, IL-23 and IFN-γ, the mRNA levels of Foxp3 and RORγt as well as the protein levels of SOCS3, JAK2, and STAT3 were remarkably down-regulated by combined therapy compared to CTX alone (54). Summarily, Chinese medicine compounds are capable of suppressing tumor development through the inhibitory effects on Tregs ( Table 2 ) ( Figure 1 ).

Chronic inflammation serves as a risk factor for cancers. Tumor-induced inflammation accelerates the enrichment and activity of inflammatory cells in tumor tissue, thereby promoting tumor progression (59). Therefore, it may be feasible to treat cancers through improving inflammation to enhance immune function by Chinese medicine compounds ( Figure 2 ). CRC was the third common cancer around the world, the morbidity of which ranked the second. Statistically, the incidence of CRC was higher in transition countries (1). Banxia Xiexin decoction (BXD) has been often applied to treat a variety of inflammatory diseases, including acute and chronic gastritis, oral ulcer, digestive ulcer, and so on. Yan et al. found that BXD enhanced the serum level of pro-inflammatory cytokines IL-1β, TNF-α and IL-6 in colon cancer-bearing nude mice and improve inflammation (60). With the popularization of the hepatitis B vaccine, the total incidence and mortality of liver cancer have been declining in the past three decades, whereas primary liver cancer still continues. HCC is the most common primary liver cancer (1). Hepatic fibrosis is the most vital hazard factor of HCC (61). Yang et al. established chronic liver fibrosis models with CCl₄ or MCD and found that CKI remarkably attenuated the infiltration of macrophages in the livers of these mice, down-regulated the expression of TNF-α and IL-6, thus alleviating the inflammatory response induced by liver fibrosis. Furthermore, Smad7 was identified as a key target of CKI in the treatment of liver fibrosis. CKI up-regulated Smad7, inhibited TNF-βR1, and suppressed TNF-β/Smad signaling pathway to prevent the development of chronic liver fibrosis and HCC (62). NHE-06 exerted a strong anti-inflammatory activity on HCC through the suppression of NF-κB/IL-6/STAT3 signaling and TGF-α and PTSG2. Meanwhile, NHE-06 strengthened the anti-tumor immunity by increasing the infiltration of immune cells and the production of IFN-γ. However, the preventive and therapeutic efficacy against HCC could be merely realized in mice with an intact immune system (63). Breast cancer has become the most common malignant tumor in the world and one of the main causes of death in females (1). Ruyiping (RYP) has been reported as a traditional Chinese medicine formula for breast cancer metastasis. Ye et al. found that in breast cancer 4T1-bearing mice, RYP combined with Platycodon grandiflorum (RP) effectively decreased the content of inflammatory marker Fibrinogen and inflammation-associated cytokines IL-6 and IL-1β in the lung tissue, improved the pulmonary inflammatory microenvironment resulted from breast cancer, and prevented the lung metastasis of breast cancer (64). According to Global Cancer Statistics 2020, lung cancer has become the most deadly malignant tumor in the world, whose morbidity ranked second among all cancers (1). Kejinyan decoction is an empirical prescription of traditional Chinese medicine for lung cancer clinically. Chen et al. reported that, after intervention with Kejinyan decoction, the inflammatory cytokines TNF-α, IFN-γ, IL-6, IL-4 and IL-13 were reduced and the survival of LLC tumor-bearing mice was prolonged (65). In short, Chinese medicine compounds could regulate the secretion of inflammatory cytokines to improve the inflammatory response in cancers.

Surgery and chemotherapy are the common treatments for cancers. However, side effects are always the major concern and limitation. Surgery tends to trigger inflammation, which leads to various unfavorable prognoses. Chemotherapy can damage the immune system even more. Therefore, Chinese medicine compounds combined with surgery or chemotherapy are typically used in clinical treatments to enhance efficacy and reduce side effects ( Figure 2 ). Transcatheter arterial chemoembolization (TACE) has been identified as one of the therapies for HCC (66). Dai et al. reported DZP combined with TACE enhanced the immune functional indexes in serum and the number of CD4⁺/CD8⁺ T cells and reduced VEGF, TGF-β1 and MMP-2 to ameliorate cancer metastasis and other adverse reactions after TACE (67). A clinical trial has demonstrated that San Huang decoction remarkably reduced the volume of exudate after breast cancer surgery and the expression of TNF-α, IL-6, IL-8 and C-reactive protein (CRP) to improve the inflammation. Some studies have illustrated that Chinese medicine compounds could not only enhance the effectiveness of chemotherapy (23, 46, 48), but also alleviate the side effects of chemotherapy, including diarrhea, weight loss and other symptoms of hypoimmunity. PHY906 has been utilized for thousands of years to treat gastrointestinal diseases. In recent years, it has been developed as an adjuvant for cancer. Lam et al. found that PHY906 was capable of accelerating the infiltration of macrophages into tumors by inducing the up-regulation of macrophage cytokines hMCP1, dramatically promoted the conversion of macrophages to M1, and enhanced the anti-tumor effects of Sorafenib (68). In addition, Ciji-Hua’ai-Baosheng improved the immune function of H-22 tumor-bearing mice after treatment with chemotherapy and alleviated CTX-induced colitis, manifested as elevated lymphocytes in spleen, augmented IL-2, IFN-γ and TNF-α, and the reduced IL-6 in serum and tumor tissues (69). Similarly, Wu et al. found Gegen Qinlian decoction (GQT), a classic Chinese medicine compound widely applys to gastrointestinal inflammatory diseases, assisted the anti-tumor effects of irinotecan (CPT-11) on colon cancer. It reversed the abnormal enhancement of IL-1β, COX-2, ICAM-1, and TNF-α. Moreover, GQT relieved diarrhea in CPT-11-treated patients by restraining hCE2 (70). Tumor suppressor p53 has been considered to be able to regulate immunity. Inactivated p53 may influence the effects of BMCs and T cells (71). Wei et al. reported that Yangyin Fuzheng Decoction promoted the infiltration of inflammatory cells to improve anti-tumor immunity and restore the CDDP-mediated weight loss of mice (72). Thus, Chinese medicine compounds combined with conventional therapy are expected to be a promising treatment for patients suffering from malignant tumors.

Immune checkpoints represent a series of molecules on immune cells, which are recognized as switches of immune functions. In the TME, immune checkpoints are often overexpressed or activated, leading to the paralysis of the immune system. PD-1 and its ligand 1 (PD-L1) are the pivotal immune checkpoints that promote immune escape and cancer advance. Targeting the PD-1/PD-L1 axis has been effective immunotherapy against cancer (73). The combined therapy of GQT and PD-1 blocker effectively accelerated the proliferation of CD8⁺ T cells and restored the T-cell function by up-regulating IL-2 and IFN-γ. Moreover, some Chinese medicine compounds themselves exerted blocking effects on immune checkpoints. Bu Fei Decoction adjusted the immunosuppressive TAMs in non-small cell lung cancer (NSCLC) and inhibited its tumor-promoting effect by down-regulating IL-10 and PD-L1 (74). Studies have found that the PI3K/Akt signaling pathway assisted the activation of PD-1/PD-L1 axis. Teng et al. summarized that the active ingredients of Huoxue Yiqi Recipe-2 (HYR-2) targeted PD-L1 signaling pathway in the treatment of lung cancer. HYR-2 could turn M2 to M1 through down-regulating PD-L1 that is closely associated with the blockage of PI3K/Akt signaling pathway (75). Xu et al. observed that Modified Bu-zhong-yi-qi decoction suppressed the expression of PD-L1 through blocking PI3K/Akt signaling pathway in gastric cancer, thereby up-regulating the ratio of CD4⁺/CD8⁺ T cells and the number of CD8⁺PD-1⁺ T cells as well as decreasing the proportion of PD-1⁺ Tregs induced by chemotherapy, representing as a promising therapy for gastric cancer (76). PI3Kγ is an immune checkpoint for macrophages, which can switch the polarization of macrophages to reshape immune microenvironment and control immune suppression in cancers (77). Yuan et al. reported that Modified Jian-pi-yang-zheng decoction down-regulated PI3Kγ remarkably, promoted the secretion of TNF-α and IL-1β while decreased IL-10, accelerated the conversion of M2 to M1 and the differentiation of TAMs, thus prevented the progression and metastasis of gastric cancer (78) ( Figure 2 ). Although immune checkpoint has gained great attention in tumor immunotherapy, the impacts of Chinese medicine compounds on immune checkpoints are not fully investigated.

Recently, erythroid progenitor cell (EPC) has been known as the regulator in tumor immune response. In malignant tumors, EPCs did not differentiate into mature red blood cells and have inhibitory effects on tumor immunity (79). Li et al. reported that Danggui Buxue decoction reduced the abnormal accumulation of EPCs in melanoma and accelerated EPCs to differentiate into mature red blood cells, which led to relieving anemia, enhancing tumor immune response, and inhibiting the progression of melanoma (80). Estrogen/estrogen receptor (ER) has also been considered as a possible immunotherapy target for cancers (81). There are two forms of ER, ERα and ERβ. When the increase in ERα level leads to the imbalanced ratio of ERα/ERβ or the mutation rate of ERα augments, it is more likely to induce breast cancer. XH formula has been used for the treatment of breast cancer since 1740, which suppressed the proliferation and activity of breast cancer cells in dose- and time-dependent manners. Hao et al. reported that XH formula bond to ERα and HSP90, promoting the disintegration of ERα, and blocking the transmission of ERα signaling. Through this anti-estrogen-like effect, XH formula inhibited the progression of breast tumors (82). Moreover, it was reported that Shugan Liangxue (SGLX) decoction suppressed the protein levels of ERα and 17β-estradiol (E2) target genes, c-Myc and Bcl-2, in human breast cancer cells. It was speculated that SGLX exerted inhibitory effects on ER⁺ breast cancer cells selectively (83) ( Figure 2 ).