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Abstract

Limitations in the therapies of triple-negative breast cancer, the strongest invasive subtype of breast cancer, have led to unsatisfactory clinical outcomes for patients. The efficacy of immunotherapy, an emerging treatment choice for triple-negative breast cancer, is highly related to the functional expression of each immune cell in the tumor immune microenvironment. Therefore, improving the immune response of immune cells in the tumor immune microenvironment is beneficial to enhance the effects of immunotherapy for triple-negative breast cancer clinically. There is now growing evidence that the active ingredients in traditional Chinese medicine, especially herbal medicine can influence the correlation of 2 major immune cell subpopulations in the tumor microenvironment of triple-negative breast cancer: tumor-infiltrating lymphocytes (T lymphocytes, B lymphocytes, Natural killer cells) and tumor-associated myeloid cells (macrophages, myeloid-derived suppressor cells, dendritic cells, neutrophils) expression of immune effect. This suggests that traditional Chinese medicine can effectively improve the immunosuppressive state of tumor microenvironment and enhance the effects of clinical immunotherapy for triple-negative breast cancer.

Keywords

traditional Chinese medicine triple-negative breast cancer tumor microenvironment immunosuppression immune cells

Introduction

Breast cancer is the most common malignant tumor endangering women’s health.¹ The latest statistics from the International Agency for Research on Cancer show that in 2022, breast cancer in women will account for 11.6% of all new cancers, second only to lung cancer, and its deaths will account for 6.9% of all cancer deaths.² Triple-negative breast cancer (TNBC) is a subtype of breast cancer that lacks expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2), and accounts for 10% to 15% of all breast cancer cases; metastasis and recurrence are common clinically, with a very poor prognosis.³ Current therapies are mainly based on surgery, chemotherapy and radiotherapy.⁴ These therapies play a role in directly eliminating tumor cells, but the clinical efficacy is limited by the high heterogeneity of TNBC.⁵ The formation and development of breast cancer is not only the independent proliferation of tumor cells, but also highly related to the interaction with the tumor microenvironment (TME).⁶ Immune infiltration in the TME is pivotal in tumorigenesis, development and metastasis, which affects the clinical effects, and prognosis of patients.⁷

Tumor immunotherapy is based on the body’s immune response, on the one hand, to enhance the antigenicity of the tumor cells, and on the other hand, to activate or restore the normal function of the immune cells, so as to enhance the immune response, inhibiting the growth of tumor cells.⁸ The application of immune checkpoint inhibitors provides a new option for TNBC immunotherapy, but there are still some limitations in terms of efficacy and toxicity.^9,10 The efficacy of tumor immunotherapy is mainly influenced by the TME.¹¹ Normally, the body’s immune cells are able to identify and kill tumor cells, but the anti-tumor immune response in the TME is suppressed due to direct or indirect interference by tumors, which is mainly manifested in the suppression of anti-tumor immune cell effect.¹² At the same time, deleterious stimuli such as hypoxia, hyperosmolarity, acidic environment and a large number of inflammatory cytokines in the TME promote the formation of the immunosuppressive microenvironment.¹³ TNBC is currently considered to be the most immunogenic breast cancer subtype, and the formation of the immunosuppressive microenvironment contributes to the occurrence of its immune escape.¹⁴ Therefore, it is essential to further increase breast cancer immunogenicity and modulate the tumor immune microenvironment to enhance effect of tumor immunotherapy.¹⁵

The current view is that herbal extracts and certain herbal compounds in traditional Chinese medicine (TCM) can activate the immune response by regulating immune cells and their effects, reversing the immunosuppressive microenvironment.^11,16
-18 In the TCM immuno-oncology database, after comparing and analyzing 400 tumor immune targets and their large number of related ligands from different literatures with the integrated 16 437 unique TCM active ingredients, it was found that 68% to 88% of the herbal ingredients had as much as 70% to 80% similarity with at least 1 of the ligands, which proves the active role of TCM in the regulation of immune function role.¹⁹ In this paper, starting from the special immune microenvironment of TNBC, we discuss the effects of TCM on different immune cell components in the immune microenvironment, which will provide ideas for future research and application of TCM in reversing the immunosuppressive microenvironment of TNBC.

Characterization of the Immune Microenvironment and Immune Cell Components in TNBC

TNBC has the highest percentage of immune cell infiltration among all subtypes of breast cancer, and therefore it more often expresses targeted cellular molecules associated with immunotherapy response.²⁰ Dominant among these are tumor-infiltrating lymphocytes (TILs), which are closely linked to breast cancer expression and prognosis, and are important in immunotherapy.²¹ A systematic study by Stanton et al²² of nearly 14 000 breast cancer patients indicated that TNBC were the most commonly infiltrated by TILs, accounting for approximately 20% of lymphocyte-dominant breast cancer. The composition of TILs mainly incorporates T-lymphocytes (T cells), B-lymphocytes (B cells), and Natural killer (NK) cells, and the different immune cells mediate each other and affect tumor cells in different ways, exerting an anti-tumor growth or pro-tumor growth effect.²³ Among them, T-cell infiltration is more prominent in TNBC than in other breast cancer subtypes.²⁴ Based on cell surface CD expression, T cells are separated into 2 major groups: CD4+T cells (recognizing MHC-class II molecularly restricted antigens) and CD8+T cells (recognizing MHC-class I molecules on the surface of target cells with antigenic conjugates).²⁵ In the tumor immune microenvironment, CD8+T cells as cytotoxic T cells can directly kill tumor cells, while CD4+T cells are helper T cells that can be divided into different subpopulations involved in immune regulation.²⁶ CD4+T cells can differentiate to form 2 key effector subpopulations, Th1 and Th2 cells, which antagonize each other through specific cytokine secretion to maintain immune homeostasis. When the Th1/Th2 balance is dysregulated, it leads to the formation of an immunosuppressive microenvironment, which in turn promotes tumor immune escape and disease progression.²⁷ Regulatory T cells (Tregs) belong to another particularized subpopulation of CD4+T cells, which inhibit T cell activation and cytokine production to suppress the body’s normal immune response.²⁸ In contrast, B cells in the tumor immune microenvironment are mainly responsible for antigen presentation and antibody production to T cells, and ensure that the effects of other immune cells act on the same target.²⁹ NK cells, as innate immune cells, not only kill cancer cells directly, but also coordinate anti-tumor immune responses through mutual mediation with other cells.³⁰ It has even been shown that tumor immune infiltration of TNBC subtypes is closely associated with higher NK cell infiltration.³¹

In addition to the dominant TIL immune cell subpopulation, there is another immune cell subpopulation in the TNBC immune microenvironment. Another cell immune subpopulation was named tumor-associated myeloid cells (TAMCs), which can be divided into tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), dendritic cells (DCs), and tumor-associated neutrophils (TANs), with TAMs and MDSCs being the most abundant tumor-immune infiltrating cells.³² TAMs can be usually separated into 2 phenotypes: M1 and M2, with the former having antitumor effects, while the latter usually exhibits pro-tumorigenic features.³³ Myeloid-derived suppressor cells are derived from pathologically activated neutrophils and monocytes and have strong immunosuppressive activity,³⁴ mainly manifested as inhibition of T cell activation and proliferation.³⁵ DCs are an innate immune cell with the strongest antigen presentation function, which can efficiently uptake, process and deliver antigens, and are involved in innate and adaptive immunity.³⁶ However, due to the immunosuppressive microenvironment, DCs often exhibit a markedly dysfunctional state, which ultimately leads to impaired anti-tumor immune responses.³⁷ As one of the major cellular components of tumor-associated immune cells, TANs have been shown to have functional plasticity in the TME, which is not only associated with the formation of an immunosuppressive microenvironment that promotes tumor progression and metastasis, but can also work together to exert an anti-tumor immune response through direct killing of tumor cells and coordinated action with other immune cells.³⁸ In addition to this, activated TANs in the TME of TNBC form higher levels of neutrophil extracellular traps (NETs)—extracellular fibrous networks consisting of depolymerized chromatin DNA frameworks and several antimicrobial proteins—than other subtypes, which have the undesirable effect of promoting tumor growth and metastasis and suppressing antitumor immunity.³⁹

As the most immunogenic subtype of all breast cancer, TNBC is characterized by a higher infiltration of TILs (incorporating T cells, B cells, NK cells) compared to other breast cancer subtypes, with T cells predominantly infiltrating the immune system, which plays the role of the main immune response to antitumor effects. And it has the effective infiltration of TAMCs, mainly TAMs and MDSCs, as well as TANs and DCs. On the one hand, in the TME of TNBC, some of the activated immune cells can play a role in recognizing and killing tumor cells; on the other hand, certain immunosuppressive cells may reverse the suppression of the immune response and promote immune escape from the tumor, resulting in tumor growth and metastasis (Figure 1). The purpose of immunotherapeutic intervention is to allow the immune cells in the TME to release the inhibitory state, attenuate their tumor-promoting growth, develop in the direction of recognizing and killing tumor cells, and improve anti-tumor immune vitality, so as to achieve the purpose of self-elimination of tumors within the organism.

Figure 1.

Immune cell components of the immune microenvironment in TNBC.

Effects of TCM on TCLs in the Immunosuppressive Microenvironment of TNBC

T Cells

The highly immunosuppressive nature of TAMs is mainly achieved by inhibiting anti-tumor T cells.⁴⁰ Therefore, the functional expression of T cells is the key to the efficacy of tumor immunotherapy.⁴¹ An animal experimental study showed that Icariin, a natural isoprenylated flavonol glycoside extracted from the Chinese herbal medicine Epimedium, could promote SIRT6 expression, inhibit the NF-κB signaling pathway, and noticeably improve the infiltration of CD4+T and CD8+T cells and strengthen enhanced anti-tumor immune response in a mouse model of TNBC (4T1 mice) with breast cancer.⁴² Another animal experiment showed that Solanum nigrum polysaccharide affected the proliferation of CD4+, CD8+T cells in vivo by activating the TLR4 signaling pathway.⁴³ Hirsutella sinensis fungus, produced after processing with Cordyceps sinensis, was shown to reduce apoptosis of CD8+T cells in vitro and in vivo by inhibiting the transcription factor T-Bet on CD8+T cells, thus promoting the proliferation of CD8+T cells and improving the secretion of potent factors like IFN-γ and granzyme B.⁴⁴ Studies have shown that compounds made using Salvia miltiorrhiza lactone extracted from Salvia miltiorrhiza can stimulate the expression of molecules such as IFN-γ, granzyme B, and TNF-α, activate the function of CD8+T cells and reduce the depletion of T cells both in vitro and in vivo, and show good antitumor effects.⁴⁵ The in vitro cellular experiments of Wang et al⁴⁶ demonstrated respectively that the combination of oxymatrine and astragaloside IV had enhanced T-cell activation, and in vivo animal experiments in the same period demonstrated that the combination of them could further improve the infiltration of CD4+T and CD8+T cells in TNBC, promoting IFN-γ, and granzyme B secretion and improving the immune effect.

In addition to tumor immune escape caused by insufficient T-cell infiltration, Th1/Th2 imbalance CD4+T cells is a common factor, which is strongly linked to the occurrence, development, and prognosis of TNBC.²⁷ Radix bupleuri, a common Chinese medicine, was shown in an in vivo animal study to inhibit breast cancer growth by its active ingredient, Saikosaponin A, which not only increases CD8+T cells and CD4+T cells infiltration but also promotes the Th1/Th2 balance toward Th1 response through partial activation of the IL-12/STAT4 pathway.⁴⁷ Another in vivo animal study suggests that low molecular weight Glycyrrhiza polysaccharide may generate an immune response by down-regulating the ERK/p38/NF-κBp50 pathway, elevating the IFN-γ/IL-4 ratio, and tilting the Th1/Th2 balance toward Th1.⁴⁸ In addition, the study of combining TCM with other therapeutic approaches to enhance T cell-related immune function is also emerging. Some studies have indicated that Andrographolide combined with PD-1 blockade immunotherapy enhances the infiltration of CD4+T and CD8+T cells and promotes the secretion of IFN-γ, FasL, perforin, and granzyme B to promote the activation of T cells and inhibit tumor proliferation in animals.⁴⁹ Researchers have also developed a liposomal silybin encapsulating the herbal ingredient silymarin in recent years, suggesting that it may significantly increase CD8+T cell infiltration in the TME of 4T1 mice through inhibition of the NF-κB pathway alteration, thereby reversing the immunosuppressive microenvironment.⁵⁰

Regulatory T cells (Tregs) in TILs are immunosuppressive cells involved in the maintenance of body immune homeostasis and autoimmune tolerance.⁵¹

Artemisinin, discovered by Nobel laureate Tu Youyou, which has antimalarial effects, is an active ingredient extracted from the Chinese herb Artemisia annua, and modern research has found that it also has some efficacy in tumor immunomodulation. Studies have shown that artemisinin can significantly increase the levels of IFN-γ and TNF-α in tumors, and significantly reduce the level of TGF-β to eliminate Treg immunosuppression in tumors of 4T1 mice, and promote T-cell activation to impede the growth of 4T1 tumors in vivo.⁵² The classical Chinese medicine formula Xihuang pill achieves antitumor effects by inhibiting the expression of PI3K and AKT pathways on Tregs in 4T1 mice tumors and upregulating AP-1 expression, promoting Treg cell apoptosis, reducing its immunosuppressive effect on the TME, thus activating T cell immune function and achieving anti-tumor effect.⁵³ Similarly, in another 4T1 mice experiment, it was verified that a Chinese herbal formula, Aiduqing, prevented naive CD4+T from differentiating into Tregs by inhibiting the TAM/CXCL1 signaling pathway, thereby improving immunosuppression and inhibiting tumor growth.⁵⁴ However, the active ingredients in these TCM prescriptions and formulas are still unclear and need to be further explored in subsequent studies.

From this we conclude that the effects of TCM on T cells in the immune microenvironment are mainly manifested as (1) promoting T-cell activation and stimulating CD8+T cells to enhance their direct tumor cell killing function; (2) correcting the state of Th1/Th2 imbalance in CD4+T cells, so that Th2-type cells will be transformed into Th1-type cells to achieve the anti-tumor effect; (3) inhibiting the immune suppressive cells-Treg cell proliferation, prompting its apoptosis. Due to the close connection between the various subtypes of T-cells, the specific targets of some TCM components still need to be further investigated to clarify the mechanism of action and to prove the effectiveness of TCM in improving the immune function of T cells more precisely.

B Cells

Current research evidence suggests that the effect of tumor-infiltrating B lymphocytes (TIL-B), including B cells and plasma cells (PCs), in the anti-tumor immune response cannot be ignored, and this role is mainly manifested in the synergistic function of other immune cells, and the effective infiltration of TIL-B is crucial for the activation of immune function.^55,56

In an in vitro cellular assay, Pueraria lobata polysaccharide, an active ingredient of Chinese herbal medicine Pueraria lobata, was shown to increase the secretion of the B-cell-promoting factor IL-4, which improves the proliferation and activation of B cells and exerts its antigen-presenting effect on T cells.⁵⁷ This indicate that the effects of TCM on B cells are mainly manifested in enhancing the proliferation and activation function of B cells to better antigen presentation to T cells to achieve anti-tumor effects; due to the limitations of in vitro cell culture, there is a lack of research on the components of TCM targeting B cells, and the specific active ingredients and related targets of its effects on B cells still need to be further investigated, which can be combined with in vivo experiments to discover the effects of TCM in the complete immune system on B cells.

NK Cells

NK cells are innate immunotoxic cells, and while mature NK cells in the TME have anti-tumor effects, immature NK cells present in TNBC promote tumor progression.⁵⁸ Evidence suggests that activation of NK cells is beneficial in enhancing anti-tumor capacity.⁵⁹

An in vitro cellular experiment revealed that resveratrol, which exists in various Chinese medicinal plants, can activate the immune response of NK cells and play an anti-tumor role by activating the AKT and mTORC2 pathways to up-regulate the production of c-Myb factor and increase the expression of NKp30a, NKp30b, and other ligands.^60,61 Another in vitro cell co-culture assay demonstrated that Ginsenoside Rh2 could enhance the killing function of NK cells by activating the NKG2D-MICA signaling axis, thus achieving anti-breast cancer effects.⁶² Tanshinol has also been found to play an anti-tumor role in breast cancer by enhancing the NKG 2DL-NKG 2D pathway, which can restore the tumor-killing activity of NK cells in vivo and in vitro.⁶³ And Verbena officinalis extract may promote the tumor killing activity of NK cells by inhibiting the signaling of NKG2A and KIR2DL1.⁶⁴

In summary, the effects of TCM on NK cells are mainly reflected in (1) enhancing the tumor-killing ability of NK cells and exerting the tumor immunocidal function; (2) promoting the proliferation ability of NK cells. Since un-activated NK cells will have the adverse effect of promoting tumor progression, the research of TCM on NK cells can focus on the mechanism of activating their anti-tumor killing ability to exert its beneficial function of killing tumor cells. The effects and mechanisms regarding the effective herbal components contained in TCM on the subpopulation of TCLs in tumor immune cells are summarized in Figure 2 and Table 1.

Figure 2.

Targets related to the action of traditional Chinese medicine on TILs.

Table 1.

Role of Traditional Chinese Medicine on TILs.

Source	Effective constituent	Mechanism of action	Result	References
Saponins
Icariie	Icariin	SIRT6↑ NF-κB↓	CD4+T↑ CD8+T↑	Song et al⁴²
Matrine/Astragalus	Combination of oxymatrine and astragaloside IV	IFN-γ↑ Granzyme B↑	CD4+T↑ CD8+T↑	Wang et al⁴⁶
Radix bupleri	Saikosaponin A	IL-12/STAT4↑	Th 1↑ Th2↓	Zhao et al⁴⁷
Ginseng	Ginsenoside Rh2	NKG2D-MICA↑	NK cells↑	Yang et al⁶²
Polysaccharides
Solanum nigrum	Solanum nigrum polysaccharide	TLR4↑	CD4+T↑ CD8+T↑	Pu et al⁴³
Glycyrrhiza	Glycyrrhiza polysaccharide	ERK/p38/NF-κBp50↓	Th 1↑ Th2↓	Song et al⁴⁸
Glycyrrhiza	Glycyrrhiza polysaccharide	IFN-γ/IL-4↑	Th 1↑ Th2↓	Song et al⁴⁸
Pueraria lobata	Pueraria lobata polysaccharide	IL-4↑	B-cells↑	Cai et al⁵⁷
Terpenes
Salvia miltiorrhiza	Salvia miltiorrhiza lactone	IFN-γ↑ Granzyme B↑ TNF-α↑	CD8+T↑	Zhang et al⁴⁵
Andrographis	Andrographolide	IFN-γ↑ FasL↑ Perforin↑ Granzyme B↑	CD4+T↑ CD8+T↑	Liu et al⁴⁹
Artemisia annua	Artemisinin	IFN-γ↑ TNF-α↑ TGF-β↓	Tregs↓	Cao et al⁵²
Alcohols
Polygonum cuspidatum	Resveratrol	AKT↑	NK cells↑ c-Myb↑ NKp30a↑ NKp30b↑	Lee and Kim⁶⁰ and Lee et al⁶¹
Polygonum cuspidatum	Resveratrol	mTORC 2↑	NK cells↑ c-Myb↑ NKp30a↑ NKp30b↑	Lee and Kim⁶⁰ and Lee et al⁶¹
Salvia miltiorrhiza	Tanshinol	NKG2DL-NKG 2D↑	NK cells↑	Yang et al⁶³
Others
Cordyceps sinensis	Hirsutella sinensis fungus	T-bet↓ IFN-γ↑ Granzyme B↑	CD8+T↑	Jin et al⁴⁴
Verbena	Verbena officinalis extract	NKG2A↓ KIR2DL1↓	NK cells↑	Dai et al⁶⁴
Silymarin	Liposomal silybin	NF-κB↓	CD8+T↑	Wu et al⁵⁰
Compounds
Xihuang pill	Xihuang pill	PI3K/AKT↓ AP-1↑	Tregs↓	Li et al⁵³
Aiduqing	Aiduqing	TAM/CXCL1↓	Tregs↓	Li et al⁵⁴

Abbreviations: SIRT6, sirtuin 6; NF-κB, nuclear factor-κB; IFN-γ, interferon-γ; IL-12/STAT4, interleukin-12/signal transducer and activator of transcription 4; NKG2D-MICA, natural killer cell group 2D/MHC class l chain-relatedmolecules A; TLR4, toll-like receptor 4; ERK/p38/NF-κBp50, extracellular regulated protein kinases/mitogen-activated protein kinase-38/nuclear factor-κB-50; IL-4, interleukin-4; PI3K/AKT, phosphatidylinositol 3 kinase/protein kinase B; TNF-α, tumor necrosis factor α; T-bet, T-box expressed in T cell; TGF-β, transforming growth factor-β; mTORC2, mammalian target of rapamycin-C2; NKG2DL, ligand of natural killer cell group 2D; NKG2A, natural killer cell lectin-like receptor subfamily C member; KIR2DL1, killer cell immunoglobulin-like receptor 2DL1; PI3K/AKT, phosphatidylinositol 3 kinase/protein kinase B; AP-1, activator protein-1; TAM/CXCL1, receptor tyrosine kinases(Tyro3.Axl.Mer)/melanoma growth stimulating activity, alpha; c-Myb, recombinant transcriptional activator Myb; NKp30a/NKp30b, natural killer T-cell receptor protein 30(a/b); T cells, T lymphocytes; CD4+, helper T lymphocytes; Th1/Th2, 2 key subpopulations of helper T lymphocytes; CD8+, cytotoxic T lymphocytes; Tregs, regulatory T cells; B cells, B lymphocytes; NK cells, natural killer cells;↑, promote; ↓, inhibit.

Effects of TCM on TAMCs in the Immunosuppressive Microenvironment of TNBC

TAMs

The expression of M1 subtype and M2 subtype in TAMs depends on the stimulatory signals they receive from the tumor microenvironment.⁶⁵ In TME, most macrophages exhibit an immunosuppressive phenotype (M2) that promotes tumor proliferation, invasion, and metastasis by suppressing the tumor immune microenvironment.⁶⁶ Therefore, there is a clinical need to eliminate TAM-mediated immunosuppression and induce activation of the M1 phenotype to achieve an antitumor immune response in the immune microenvironment.⁶⁷

An in vitro cellular assay demonstrated that Dandelion extract could promote TAM polarization from M2 to M1 phenotype, and its specific pathway of action might be related to attenuating immunosuppression of IL-10/STAT3/PDL1 signaling pathway.⁶⁸ An animal experiment demonstrated that a tansy extract, Cryptotanshinone, increased cytokine secretion including TNF-α, IL-12a and IL-12b, decreased cytokine expression including IL-1b and IL-10, promoting M1 phenotypic expression, and inhibited tumor proliferation.⁶⁹ Smilax glabra Roxb ethyl acetate significantly inhibited the M2 phenotype of macrophages in vitro by down-regulating HIF-1 pathway protein expression, prompting their polarization to M1.⁷⁰ Another study demonstrated that Pulsatilla saponins similarly inhibited M2 macrophage polarization and suppressed tumor progression in vitro by inhibiting the IL-4/STAT6 signaling pathway.⁷¹ Caffeic acid is an active ingredient present in a variety of Chinese medicinal plants, and a semi-in vivo experiment found that Caffeic acid induces macrophage polarization from M2 to M1 in mouse splenocytes and enhances anti-tumor immune responses by affecting the FOXO1/FIS signaling pathway and decreasing the expression of FOXO1.⁷² A novel polysaccharide isolated from Coriolus versicolor can polarize the M2 phenotype to the M1 phenotype in vitro and in vivo in mice by a mechanism that may be linked to the activation of AKT, JNK and NF-κB pathways.⁷³ These active ingredients extracted from different herbs are beneficial for TAM anti-tumor immunomodulation in TNBC.

The above study illustrates that the effects of TCM on TAMs are (1) inhibiting the M2-related signaling pathway to promote its polarization to the M1 phenotype; (2) activating the M1-related signaling pathway to release the immune suppression and exert the immune response, thus killing tumor cells. Since the 2 phenotypes of TAMs often coexist in the TME, the effective transformation between them is the key to stimulating its anti-tumor ability, and it is precisely the goal of many active ingredients in TCM to enhance the immunocidal function of TME by fully activating the cellular function of the M1 phenotype of its effective immune response.

MDSCs

MDSCs are one of the immunologically active suppressor cells in the TME with strong immunosuppressive effects that hinder the anti-tumor immune response.⁷⁴ Recent studies have shown that the therapeutic targeting of MDSCs has promising prospects in remodeling the immunosuppressive microenvironment and improving cancer immune efficacy.⁷⁵ Lots of TCM ingredients have obvious inhibitory effects on their proliferative activities.

Extracts of polysaccharides from the herb Polygonatum sibiricum have been shown to possess a variety of biological activities, such as antidiabetic, anti-inflammatory, antioxidant, immunomodulatory, and anticancer effects, which can be induced by lowering the level of G-CSF to increase the percentage of the subpopulation of MDSCs in 4T1 mice.⁷⁶ An in vitro experiment by Zhang et al⁷⁷ found that Asparagus polysaccharide significantly inhibited the proliferation of MDSCs by activating the TLR4 pathway, and attenuated the immunosuppressive state. Studies have shown that the extract of Chinese herbal medicine Prim-O-glucosylcimifugin can attenuate the proliferation, metabolism and immunosuppression of MDSCs in vitro and in vivo by inhibiting the tricarboxylic acid cycle (TCA).⁷⁸ Neobavaisoflavone, a flavonoid compound extracted from the Chinese herbal medicine psoralen, inhibits the proliferation, and attenuates the inhibitory function of MDSCs in 4T1 mice in vivo by inhibiting STAT3 signaling.⁷⁹ Another animal study reported that the Chinese herbal compound Baoyuan Jiedu decoction suppressed the number of MDSCs in 4T1 mice by inhibiting the TGF-β/CCL-9 pathway, which would potentially reduce the risk of lung metastasis from breast cancer.⁸⁰ All of these herbal single components or compound preparations can effectively inhibit the activity of MDSCs and improve the state of immunosuppression.

Since the immunosuppressive effects of MDSCs are important in the immunosuppressive microenvironment of breast cancer, and the clinical focus is on lifting this state of suppression. The effect of TCM on MDSCs is mainly manifested in the inhibition of their proliferative activity and the induction of apoptosis, to reduce its suppressive effects on immune function and restore the immune response to the normal level in the TME, thus prompting other immune effector cells to give full play to their killing function and kill the tumor.

DCs

DCs are the major antigen-presenting cells in the human body. They have the ability to have highly efficient antigen presentation and cross-presentation activities, as well as a strong T-cell initiating capacity.⁸¹ Therefore, promoting the maturation of DCs in tumor patients is conducive to increasing the activation capacity of T cells and greatly improving the immunocidal function against cancer cells, which is an effective strategy for anti-tumor immunotherapy.⁸²

Astragalus polysaccharide is the main component of Chinese herbal medicine Astragalus, which has been found in numerous studies to stimulate the expression of the DC surface molecules CD80 and CD86, thereby promoting the maturation of DCs and activating cytotoxic T-cells to play an anti-tumor effect.⁸³ An in vivo experiment in 4T1 mice found that Huaier extractum can promote the maturation of DCs through activation of the PI3K/AKT pathway, which will contribute to the T-cell immune response.⁸⁴ Other studies have shown that Plantago lanceolata polysaccharide stimulates the expression of CD86, CD80 and MHC II both in vivo and in vitro, promotes the maturation of DCs phenotype and function, stimulates the proliferation of immune cells, and thus inhibits the growth of breast tumor cells.⁸⁵

In short, the effects of TCM on DCs are mainly reflected in inducing their maturation, giving full play to their antigen-presenting effect on T cells, prompting the activation of T cells, and exerting their immune recognition and response functions to kill tumors for the purpose of immunotherapy for TNBC.

TANs

Existing studies have shown that TANs have emerged as one of the targets for breast cancer immunotherapy, and that they can be polarized to anti-tumor (N1) or pro-tumor (N2) phenotypes in the tumor immune microenvironment.⁸⁶ In addition, neutrophil extracellular traps(NETs) were shown to be inhibitory to tumor immunotherapy.⁸⁷

TCM research targeting TANs is also emerging and has made some degree of progress. Dihydrotanshinone I, an extract of the Chinese herb Salvia miltiorrhiza, has been shown to inhibit breast cancer lung metastasis by effectively reducing TANs infiltration and neutrophil extracellular trap formation in 4T1 mice through inhibition of TIMP1 expression.⁸⁸ Several studies have shown that Platycodin D, an active ingredient extracted from the herb Platycodon grandiflorus, can further inhibit pulmonary metastasis of TNBC by inhibiting the PI3K/AKT signaling pathway and promoting neutrophil apoptosis in 4T1 mice.⁸⁹

It can be seen that the effects of TCM on TANs are mainly reflected in (1) Inhibiting the proliferation and vitality of TANs, alleviating the occurrence of immunosuppression, and promoting the activation of the normal immune response of other immune cells, thus killing tumor cells. (2) Promoting their maximum possible polarization to N1 phenotype and exerting anti-tumor immune effects. However, the current study is relatively limited, and the specific mechanism of the role of TCM on TANs in the TNBC immune microenvironment needs to be further explored. The effects and mechanisms regarding the effective herbal components contained in TCM on the subpopulation of TAMCs in tumor immune cells are summarized in Figure 3 and Table 2.

Figure 3.

Targets related to the action of traditional Chinese medicine on TAMCs.

Table 2.

Role of Traditional Chinese Medicine on TAMCs.

Source	Effective constituent	Mechanism of action	Result	References
Saponins
Pulsatilla	Pulsatilla saponins	IL-4/STAT6↓	M2↓ M1↑	Yang et al⁷¹
Platycodon grandiflorus	Platycodin D	PI3K/AKT↓	TANs↓	Ye et al⁸⁹
Polysaccharides
Coriolus versicolor	A novel polysaccharide isolated from Coriolus versicolor	AKT↑	M2↓ M1↑	Bi et al⁷³
		JNK↑
		NF-κB↑
Polygonatum sibiricum	Polysaccharides from Polygonatum sibiricum	G-CSF↓	MDSCs↓	Xie et al⁷⁶
Asparagus	Asparagus polysaccharide	TLR4↑	MDSCs↓	Zhang et al⁷⁷
Astragalus	Astragalus polysaccharide	CD80↑CD86↑	DCs↑	Wang et al⁸³
Plantain herb	Plantago lanceolata polysaccharide	CD86↑CD80↑MHC II↑	DCs↑	Pan et al⁸⁵
Quinones
Salvia miltiorrhiza	Cryptotanshinone	TNF-α↑IL-12a↑IL-12b↑	M2↓ M1↑	Yen et al⁶⁹
Salvia miltiorrhiza	Cryptotanshinone	IL-1b↓IL-10↓	M2↓ M1↑	Yen et al⁶⁹
Salvia miltiorrhiza	Dihydrotanshinone I	TIMP1↓	TANs↓	Zhao et al⁸⁸
Esters
Smilax glabra Roxb	Smilax glabra Roxb ethyl acetate	HIF-1↓	M2↓ M1↑	Guo et al⁷⁰
Organic acids
Dandelion/Honeysuckle	Caffeic acid	FOXO1/FIS↓	M2↓ M1↑	Xie et al⁷²
Flavonoids
Rhizoma cimicifugae	Prim-O-glucosylcimifugin	TCA↓	MDSCs↓	Gao et al⁷⁸
Coumarins
Fructus psoraleae	Neobavaisoflavone	STAT3↓	MDSCs↓	Guo et al⁷⁹
Others
Dandelion	Dandelion Extract	IL-10/STAT 3/PDL1↓	M2↓ M1↑	Deng et al⁶⁸
Huaier	Huaier extractum	PI3K/AKT↑	DCs↑	Pan et al⁸⁴
Compounds
Baoyuan Jiedu decoction	Baoyuan Jiedu decoction	TGF-β/CCL-9↓	MDSCs↓	Tian et al⁸⁰

Abbreviations: IL-4/STAT6, interleukin-4/signal transducer and activator of transcription 6; PI3K/AKT, phosphatidylinositol 3 kinase/protein kinase B; JNK, c-Jun N-terminal kinase; NF-κB, nuclear factor-κB; G-CSF, granulocyte colony stimulating factor; TLR4, toll-like receptor 4; CD80, T-lymphocyte activation antigen CD80; CD86, T-lymphocyte activation antigen CD86; MHC II, major compatibility complex II; TNF-α, tumor necrosis factor α; IL-12a, interleukin-12a; IL-12b, interleukin-12b; IL-1b, interleukin-1b; TIMP1, tissue inhibitor of metalloproteinases-1; HIF-1, hypoxia inducible factor-1; FOXO1/FIS, forkhead box protein O1/fission; TCA, triose carbonate cycle; IL-10/STAT3/PDL1, interleukin-10/signal transducer and activator of transcription 3/programed cell death-ligand 1; TGF-β/CCL-9, transforming growth factor-β/recombinant mouse C-C motif chemokine 9; TAMs, tumor-associated macrophages; M1/M2, 2 phenotypes of Tumor-associated macrophages; MDSCs, myeloid-derived suppressor cells; DCs, dendritic cells; TANs, tumor-associated neutrophils; N1/N2, 2 phenotypes of tumor-associated neutrophils; ↑, promote; ↓, inhibit.

Conclusion and Future Perspective

TNBC is considered to be the most immunogenic of all breast cancer subtypes, and immunotherapy has become one of its common clinical treatments. However, its efficacy is affected by immunosuppression in the TME, which is mainly caused by the suppression of the function of multiple immune cells in the TME. Alleviating the immunosuppressive state in the TME of TNBC is currently one of the main directions of immunotherapy. TCM has a history of several 1000 years of inheritance in China, and one of its therapeutic principles is “nourishing positive accumulation and eliminating cancer by itself,” which is reflected in the way modern medicine stimulates the body’s autoimmunity to treat diseases.¹⁷ The use of TCM to regulate the function of immune cells in TNBC TME, stimulate immune response, and enhance the body’s own ability to eliminate tumor cells is a feasible therapeutic approach.

The role of TCM in regulating TNBC can be divided into 2 aspects, 1 is to promote the proliferation and functional expression of immune cells with anti-tumor immune function; the other is to inhibit the growth and activation of immune-suppressive cells with pro-tumor function. Immune cells such as CD4+T cells, CD8+T cells, B cells, NK cells in the TIL subpopulation, and DCs in the TAMC subpopulation are positively regulated by TCM and active ingredients, which promotes their proliferation and activation and exerts anti-tumor immune function. Among them, the different phenotypes of special CD4+ (Th1, Th2) were bi-directionally regulated by a variety of Chinese medicine ingredients, which were mainly manifested in promoting Th2 to Th1 polarization. In addition, TCM components also play a bi-directional regulation of TAM (M1, M2) and TAN (N1, N2) in the TAMC subpopulation, which are manifested in the promotion of the polarization of M2 to M1 in TAM and the polarization of N2 to N1 in TANs. As for Tregs in the TIL subpopulation and MDSCs in the TAMC subpopulation, which have immunosuppressive functions, TCM can inhibit their proliferation, and activation to alleviate the immunosuppression in the TME of TNBC, so that other anti-tumor immune cells can give full play to their immune functions. TCM has always had unique advantages and wide applications in the treatment of cancer. In the case of TNBC, on the one hand, the effective effects of a large number of active ingredients in TCM on TNBC-related immune cells provide us with a powerful adjuvant support for the immunotherapy of TNBC in the clinic, which can effectively improve the efficacy of immunotherapy; on the other hand, certain special effects of TCM, such as improving body quality and alleviating various discomforts caused by clinical tumor therapy drug reactions, can effectively improve the quality of life of breast cancer patients. All these may become the focus of clinical treatment for cancer patients in the future, and this basic research has laid the foundation for the possibility of clinical application.

Due to the complexity and specificity of the components of traditional Chinese medicine, the current study still has some limitations. The mechanism of TCM in regulating the immune cells in TME of TNBC is mainly manifested in the activation of anti-tumor immune cells and inhibition of immune-suppressing cells’ pathway expression. Since the immune cells in the immune microenvironment crosstalk with each other and are closely connected, the specific mechanism of action of TCM still needs to be further investigated. Whether from the complexity of the immune microenvironment itself or the holistic nature of the therapeutic aspect of TCM, our future research may focus on the study of the influence and mediating mechanism among immune cells. Considering the unknown toxicity of some of the components of TCM, most of the current studies are basic cellular and animal studies, and as the research progresses, clinical studies will also be essential. To better provide a more comprehensive, safer and more efficient theoretical basis for the use of TCM as an adjuvant therapy for immunotherapy of TNBC in the future.

Footnotes

ORCID iD

Chaoyan Wu

Consent to Participate

Not applicable as this is a review of published studies.

Author Contributions

T He designed the study and wrote the manuscript. SL Yu participated in the data collection. CY Wu provided critical feedback on the analysis and interpretation of results. All authors reviewed and approved the final manuscript.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Hubei Administration of Traditional Chinese Medicine (Grant No. ZYYCC2023002); Natural science Foundation of Science and Technology Hubei Province (Grant No.2024AFB799); Medical Innovation Platform Project of Zhongnan Hospital of Wuhan University (Grant No.PTXM2023035); Hubei Administration of Traditional Chinese Medicine Scientific Research Program (Grant No.ZY2025Z017).

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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Progress of Traditional Chinese Medicine in Regulating Immune Cell in the Tumor Microenvironment of Triple-Negative Breast Cancer

Abstract

Keywords

Introduction

Characterization of the Immune Microenvironment and Immune Cell Components in TNBC

Effects of TCM on TCLs in the Immunosuppressive Microenvironment of TNBC

T Cells

B Cells

NK Cells

Effects of TCM on TAMCs in the Immunosuppressive Microenvironment of TNBC

TAMs

MDSCs

DCs

TANs

Conclusion and Future Perspective

Footnotes

ORCID iD

Consent to Participate

Author Contributions

Funding

Declaration of Conflicting Interests

References