Advances in traditional Chinese herbal medicine and their pharmacodynamic mechanisms in cancer immunoregulation: a narrative review

Introduction

According to the International Agency for Research on Cancer (IARC), the global cancer burden was estimated to be 19.3 million new cases and 10.0 million deaths in 2020, and malignant tumors have become the first or second leading cause of death in 112 countries (1). Although the vast majority of initial cancer cells are identified and eliminated by the continuous monitor of the immune system, but some tumor cells manage to evade the monitor of the immune system or are able to limit the extent of immune killing to avoid elimination (2). As early as 2013, Chen et al. (3) proposed the concept of the “Cancer-Immunity Cycle (CIC)”, which was defined as a series of progressive events that cause an anticancer immune response leading to the killing of the cancer cell, indicating that the immune system kills tumor cells via seven steps: In the first step, neoantigens produced by cancer cells are presented and captured by dendritic cells (DCs) (step 1). Next, DCs present tumor neoantigens captured on molecules of the major histocompatibility complex (MHC)-Ι and MHC-Π to T lymphocytes (step 2) to activate the specific antigenic response of T lymphocytes (step 3). Finally, the aggregated T lymphocytes traffic to (step 4) and infiltrate the tumor bed (step 5) and bind to MHC-I via T cell receptor (TCR) (step 6), so as to specifically recognize and kill cancer cells (step 7). The dying cancer cells will again release antigens for DCs to recognize, completing the immune cycle. The realization of the cancer immune cycle is regulated by a series of stimulatory and inhibitory signals, such as the immune checkpoint proteins programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) provide inhibitory signals. Among them, the PD-1/PD-L1 pathway is an essential co-inhibitory molecular pathway mediating tumor immune escape caused by T cell depletion. Moreover, the tumor microenvironment (TME) also plays an important role in the PD-1/PD-L1 pathway. Tumor immune escape mediated by the PD-1/PD-L1 pathway is described as “adaptive resistance”, in which T cells recognize the tumor antigen MHC complex and are activated as tumor effector cells (Teff). It reaches the tumor site and becomes tumor-infiltrating lymphocytes (TILs). TILs recognize tumor antigens and produce interferon gamma (IFN-γ) and other molecules to promote the expression of PD-L1 in the tumor environment. After binding with PD-1, PD-L1 transmits anti-apoptotic signals to tumor cells through T cell inhibition signals, resulting in T cell functional inactivation and survival. With the advances in tumor immunology, the value of immune checkpoint inhibitors (ICIs) is increasingly being recognized. Anti-cytotoxic T lymphocyte-associated protein 4 (anti-CTLA-4), antibodies against PD-1 and PD-L1 have demonstrated extension of patients’ survival (4). However, the unstable and heterogeneous TME may mediate the immune escape of tumor cells and concurrently inhibit the normal immune function of the body, leading to poor clinical responses to immunotherapy in some patients. Thus, new approaches are under investigation to increase the efficacy of immunotherapy in cancer research. During thousand years’ practice, traditional Chinese medicine (TCM) has shown remarkable efficacy in treating malignant tumors. The existing basic researches have shown that TCM has significant effects on inhibiting the growth of tumor cells, enhancing the effect of radiotherapy and chemotherapy, and reducing the side effects of chemotherapy (5-7). TCM includes Chinese herbal medicine (CHM), acupuncture, etc. CHM and acupuncture have been used in cancer treatments, through immune regulation and other pathways. Acupuncture stimulation can regulate the sympathetic and parasympathetic nervous system by regulating the function of NK cells, macrophages and T lymphocytes, and produce a variety of physiological reactions including immune response. Acupuncture simulation can relieve pain, fatigue, nausea and vomiting in the treatment of patients with lung cancer, breast cancer and so on (8,9). Many clinical and basic studies on the role of CHM in regulating tumor immunity have demonstrated that some CHM monomers, CHM compound prescriptions, and CHM patent medicines can regulate the immune function of patients via multiple pathways, including immune cells, immunoactive substances, and immune organs (10,11).

The regulatory effect of CHM on CIC is mainly reflected of antigen presentation (step 1), T-cell activation (step 3), T-cell infiltration (step 5) and tumor-cell killing (step 7). This article evaluated the step 1, 3, 5 and 7 of the CIC in terms of CHM monomers, CHM compound prescriptions, and CHM patent medicines and elucidated the research progress on the pharmacodynamic mechanism of CHM in regulating tumor immunity. These represent an attempt to provide new perspectives and insights for further CHM research. We present this article in accordance with the Narrative Review reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-1983/rc).

Methods

We searched the PubMed and China National Knowledge Infrastructure (CNKI) databases for original research and review articles published in English or Chinese languages between January 1988 and October 2022. The following search terms were employed: “traditional Chinese medicine” or “Chinese medicine”, “tumor” or “neoplasm” or “cancer”, and “immune” and “immune system”. Articles cited in the relevant articles were also examined as potential sources of information. The database resources are summarized in Table 1 and Table S1.

TCM theories on tumor immunoregulation

The term “immunity” (Mian Yi) in TCM was first seen in the Mian Yi Lei Fang (or “Immune Formularies”) in the Ming Dynasty (12). It was also stated in the Notes and interpretations of the inner canon of the yellow emperor-divine pivot (by Ma Shi of the Ming Dynasty, 1586AD) that “pathogens may present, just because the vital qi is insufficient and the pathogens take the chance”. From the perspective of TCM, the occurrence and development of diseases are closely related to the status of the human body. Moreover, according to the Plain questions of the Huangdi Neijing, “When there is sufficient vital qi inside, the pathogenic qi has no way to invade the healthy body”. When the human body has balanced yin and yang and normal immune function, it can fight against and dispel pathogenic qi, and thus pathogenic qi will not cause harm to the human body. Plain questions: great theory on the law of primordial qi in nature proposed the following: “If there is the relative equilibrium of yin-yang, the essence and spirit will be well governed; and if there is a divorce of yin-yang, the essence and qi will be exhausted”. The balance between yin and yang is the foundation of health. When yin and yang become unbalanced and the vital qi becomes deficient and weak, the body’s defenses are reduced, which is reflected as immune dysfunction. As a result, pathogenic qi may afflict the human body. Therefore, a healthy or sick body depends mainly on the rise and fall of vital qi. Here the “vital qi” generally refers to the body’s ability to fight against diseases and pathogenic qi. Supposed the vital qi is not sufficient to defend the body from being beset by external pathogens. In that case, diseases will occur or progress, which is in line with the knowledge of immunity in modern medicine (13).

TCM’s understanding of the pathogenesis of a specific disease also guides its treatment. Starting from classic theories such as “harmonizing yin and yang” and “supporting the vital qi to dispel pathogenic qi”, TCM-based treatment of malignant tumors is characterized by its holistic and balanced approaches. Modern research has confirmed that TCM can regulate antitumor immunity. By regulating the TME and reshaping the immunosuppressive cells in the TME, TCM can prevent and treat tumor metastasis/recurrence and enhance the body’s immune response (14), ultimately enabling patients to live with tumors.

CHM in regulating antitumor immunity

In China, CHM is an indispensable part of multidisciplinary treatment (MDT) for tumors and can be involved in the whole-process management of patients with tumors. CHM can enhance the efficacy of conventional treatments [e.g., chemotherapy, radiotherapy and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs)] and provide synergy to enhance the sensitivity of chemotherapy drugs, reduce adverse reactions, relieve pain and improve quality of life of patients (15). We have found that most CHM herbs used for regulating antitumor immunity function as restoratives (also known as tonics) or for invigorating blood. CHM compound prescriptions are mainly used for “strengthening vital qi to eliminate pathogenic factor” or “strengthening the spleen and tonifying the kidney”. New studies have demonstrated the immune-regulating effects of some of CHM’ active ingredients (e.g., polysaccharides, glycosides, and alkaloids). CHM can regulate the tumor immune microenvironment (TIME) and the human body’s immunity in a dual manner. Chen et al. (3) proposed the concept of the “CIC”, indicating that the immune system kills tumor cells via seven steps, with each step being interconnected and iterative. Here, we summarize the currently available studies on CHM (including monomers, CHM compound prescriptions, and proprietary Chinese medicines) in CIC and their pharmacodynamic mechanisms, focusing on their roles in each CIC step.

The roles of CHM in CIC

CHM regulates antigen presentation

DCs are the most potent antigen-presenting cells (APCs) that are widely distributed in the body. However, DCs in tumors are often immature, and the immature DCs need to undergo “activation” of tumor neoantigens as well as phenotypic and functional changes before they become mature and activated. Up to 45 studies in China and abroad have reported that polysaccharides and other ingredients (e.g., ginsenoside Rg3 and curcumin) of CHM, CHM compound prescriptions (e.g., Fei-Liu-Ping ointment), and CHM patent medicines (e.g., Fei-Yan-Ning granules) can upregulate the expressions of MHC-I/II and costimulatory molecules (e.g., CD40, CD80, and CD86) on the surface of DCs through different mechanisms to promote the maturation of DCs. Meanwhile, they can also promote the secretion of cytokines such as interleukin (IL)-6, IL-12, and IL-18 to enhance antitumor activity.

Macrophages (MΦ), an integral component of innate immunity, can differentiate into either a proinflammatory (M1) subtype, also known as a classically activated subtype, or an anti-inflammatory alternatively activated subtype (M2). M1 macrophages play a vital role in promoting type 1 T helper (Th1) response and antitumor function, while M2 macrophages exert anti-inflammatory and protumor growth effects by expressing IL-10, arginase-1 (Arg-1) and other immunosuppressive cytokines (16). Research has shown that CHM monomers (e.g., ginsenoside Rh2), CHM compound prescriptions (e.g., flavored astragalus Jianzhong decoction), and CHM patent medicines (e.g., Fei-Yan-Ning granules) can promote the polarization of macrophages from M2 to M1, thus reducing M2 macrophages and increasing M1 macrophages (Table 2). Therefore, CHM can dually regulate M1 and M2 macrophages to suppress tumor cell proliferation and migration and enhance the body’s immune function.

CHM herbs regulate T-cell activation

Cytokines affecting antitumor immune response mainly derive from Th cells (including Th1 and Th2) and macrophages, among which the imbalance between Th1 and Th2 affects the growth and metastasis of various tumors (58). Upregulated expression of Th1 and downregulated expression of Th2 are associated with enhanced cellular immunity, which facilitates T-cell proliferation, activation, and infiltration and is conducive to tumor cell clearance. Some CHM including CHM monomers (e.g., polysaccharides, icariin, and Huaier extract), CHM compound prescriptions (e.g., Anfei decoction and compound yin-nourishing and yang-warming recipe), and CHM patent medicines (e.g., Xihuang pills) can induce the transformation of the immune balance and enhance antitumor immunity. In addition, the regulatory T cells (Tregs) can inhibit APCs through cytotoxic T lymphocyte antigen-4 (CTLA-4); by secreting inhibitory cytokines [e.g., IL-10, tumor growth factor-beta (TGF-β), and IL-35], expressing granzyme/perforin, and consuming IL-2, Tregs exert their immunosuppressive function, and are thus one of the major mechanisms of tumor escape from the immune system (59). Some CHM monomers and compound prescriptions can also inhibit the expression of Tregs (Table 3).

CHM herbs regulate T-cell infiltration into tumors

After the naive T lymphocytes in the lymph nodes are stimulated and activated by tumor antigens presented by APC, they begin to migrate to tumor cells through blood circulation via penetration and infiltration, to complete subsequent tumor cell recognition and killing. The key to cytotoxic T lymphocyte (CTL) infiltration within tumor bed lies in the capture, rollover, adhesion, and transendothelial migration of activated T cells, which depend on the interactions between specific adhesion molecules (e.g., selectins and integrins) and chemokines [e.g., C-X-C motif chemokine ligand (CXCL)9, CXCL10, and CXCL11] expressed on the vascular lumen and CTL surface (101). However, vascular endothelial growth factor (VEGF)-induced signaling leads to a decrease in the expressions of adhesion molecules and T cell-attracting chemokines (e.g., CXCL10 and CXCL11) by inhibiting nuclear factor-κB (NF-κB) activation in endothelial cells (102), thereby preventing T-cell migration and reducing their invasion within the tumor bed. Antiangiogenic agents can reverse this negative regulatory effect. In fact, CHM herbs can reverse the negative regulatory effect of VEGF on CTL infiltration within tumor beds by downregulating VEGF or its ligands. Zhai et al. (103) and Zhang et al. (104) have demonstrated that the turmeric extract β-elemene can downregulate VEGF; in addition, it can enhance CTL invasion within tumor beds by regulating the estrogen receptor-α (ERα)/metastasis-associated protein 3 (MTA3)/snail family transcriptional repressor 1 (SNAI1) pathway. Wang et al. (105) and Dai et al. (106) found that ginsenosides Rh2 and Rg3, two effective extracts of ginseng, downregulated VEGF and its ligand VEGF receptor (VEGFR) to reverse the negative regulation of CTL infiltration. Similarly, CHM monomers/extracts (e.g., tanshinone IIA, silybin, and Solanum nigrum L. extract) and CHM compound prescriptions (e.g., Xiaotan Sanjie decoction) can downregulate VEGF or VEGFR expression through different mechanisms. In particular, Solanum nigrum L. extract can upregulate the expression level of vascular endostatin (ES) and concurrently exert its antiangiogenetic effect, further strengthening CTL infiltration within the tumor bed (103) (Table 4).

Tumor necrosis factor (TNF) and IFN-γ, two proinflammatory cytokines, can conduce the senescence of tumor cells expressing cytokine receptors; meanwhile, they release the antiangiogenic chemokines CXCL9 and CXCL10, which ultimately leads to dormant tumors with degraded vascular supply (102). CHM monomers (e.g., polysaccharides such as licorice polysaccharides and triterpenoids from Ganoderma lucidum), CHM compound prescriptions (e.g., compound yin-nourishing and yang-warming recipe), and CHM patent medicines (e.g., Fuzheng Yiliu granules) can upregulate the secretion of TNF-α, whereas CHM monomers (e.g., β-elemene), CHM compound prescriptions (e.g., Yangyinwenyang formula), and CHM patent medicines (e.g., Huisheng oral liquid) can upregulate IFN-γ (Table 4). All of them can enhance CTL infiltration within the tumor bed by upregulating antiangiogenic chemokines.

CHM herbs regulate tumor-cell killing

The last step in CIC is killing tumor cells by immune cells. Studies have shown that CHM herbs have an absolute superiority in quantity when regulating this CIC step (73 studies; see Table 5).

CTLs are the main effector cells in this step. They are mainly derived from the direct activation of CD8⁺ T cells and have a specific killing effect on tumor cells (14). A variety of CHM polysaccharides (e.g., Epimedium koreanum polysaccharides), CHM monomers (e.g., cycloastragol), CHM compound prescriptions (e.g., Anfei decoction), and CHM patent medicines (e.g., Ganoderma applanatum polysaccharide injection) can positively regulate the killing of tumor cells by CTL in the immune circulation by upregulating CD8⁺ T cells or enhancing CTL killing ability (Table 5). CTL mainly kills tumor cells through the perforin/granzyme pathway and the death receptor pathways [Fas/Fas ligand (FasL) and TNF-α/TNF receptor]. Among them, the death receptor pathway refers to the binding of the FasL expressed by the effector CTL to the receptor (Fas receptor) on the surface of tumor cells; alternatively, the TNF-α secreted by CTL binds to TNF receptors on the surface of tumor cells, activating the signaling pathway in the cells and further inducing apoptosis of tumor cells. However, if FasL is highly expressed on the surface of tumor cells and Fas is highly expressed on the surface of CTL, CTL will become the target cell and then be killed (156). Wang et al. (37) and Pan et al. (148) confirmed that some herbal extracts and CHM compound prescriptions could regulate the antitumor immune response by regulating the expressions of perforin and granzyme. Wang et al. (141) reported that the extract of Ginkgo biloba exotesta upregulated Fas messenger RNA (mRNA) expression and downregulated FasL mRNA expression in tumor cells. In addition, there are CHM monomers, CHM compound prescriptions, and CHM patent medicines that can upregulate TNF-α secretion and thus enhance the tumor-killing effect of CTL (Table 5). In addition, Zhang (41) demonstrated that four CHM monomers (proanthocyanidins, gastrodin, baicalein, and apigenin) can promote not only the secretion of TNF-α but also enhance the killing of tumor cells by CTL through the induced expressions of perforin and granzyme.

In addition, the antibody-dependent cell-mediated cytotoxicity (ADCC) of macrophages (MΦ) and natural killer (NK) cells is another significant means of killing tumor cells and thus has become an important supplement to the final step of CIC. Immunoglobin G (IgG) mediates this effect through IgG Fc receptors on the surface of macrophages and NK cells. The ADCC effect of NK cells can be significantly enhanced by activating cytokines such as IFN-γ and IL-12 (136). Many CHM monomers (e.g., tanshinone IIA), CHM compound prescriptions (e.g., the recipe for strengthening vital qi to eliminate pathogenic factor), and CHM patent medicines (Liuwei Dihuang pill) can directly increase the amount or function of macrophages or NK cells to enhance their ADCC effect. In contrast, a variety of CHM monomers (e.g., β-elemene), CHM compound prescriptions (e.g., Yangyinwenyang formula), and CHM patent medicines (e.g., Huisheng oral liquid) can indirectly enhance the ADCC effect of NK cells by upregulating the expression of IFN-γ and IL-12 (Table 5).

Tumor cells can inhibit the body’s killing of tumor cells by actively inducing tumor-bearing bodies to produce Tregs and myeloid-derived suppressor cells (MDSCs), achieved mainly by secreting immunosuppressive factors such as TGF-β1 and IL-10 (157). CHM monomers/compounds, CHM compound prescriptions, and CHM patent medicines, represented by lentinan, Gansui root-Pinellia tuber decoction, and Fuzheng Yiliu granules, respectively, can reverse such immunosuppression by downregulating the amount or function of Tregs or MDSCs. Meanwhile, CHM monomers and CHM compound prescriptions can directly downregulate the secretion of immunosuppressive factors TGF-β1 and IL-10, as demonstrated by Cui et al. in a series of studies (126-128,137) (Table 5).

The interaction between PD-1 and PD-L1 on T cells can lead to T cell anergy, exhaustion, and apoptosis. For one, the activation of PD-1/PD-L1 signaling pathway transmits inhibitory signals to tumor cells, promoting tumor cells to resist immune effector cell-mediated apoptosis (158); for another, it suppresses the immune cell secretion of proinflammatory factors such as IFN-γ, promotes the secretion of immunosuppressive molecules such as IL-10 to suppress T-cell immune response (159,160), and even induces apoptosis (161), thereby mediating immune escape. Blocking PD-L1/PD-1 binding can relieve the inhibition of the effector T cells (14). A total of 6 studies (Table 5) reported that CHM herbs (mainly CHM monomers) regulate PD-1/PD-L1 expression through multiple pathways, thereby regulating the killing of tumor cells by the immune system.

Discussion

The studies listed in Tables 2-5 have proven that CHM and its active ingredients can enhance the body’s immune function, reduce toxicities, and increase efficiency through the second, third, fifth and seventh steps in CIC. As can be seen from the above tables, different CHM can act on different receptor cells and result in different effects. Heat-clearing and detoxicating medicine plays a role in anti-tumor by regulating cancer-associated fibroblasts and extracellular matrix. Supplementing medicine exerts its anti-tumor effect by targeting tumor-associated immune cells in the TME, while qi-rectifying and blood-invigorating medicine targets the hypoxic and acidic environment in TME. However, the currently available studies have the following limitations: First, most of the research focused on the roles of CHM herbs in regulating immune cells and the expressions of immune factors, and the specific CIC steps targeted by CHM herbs were poorly investigated. Therefore, it is important to carry out research on the targets and mechanisms of CHM herbs regulating CIC. Second, most studies on the regulation of CIC by CHM herbs were performed on the level of systemic immunity, with little evidence of local immunity. In fact, CHM antitumor therapies are based on the combination of holistic view and syndrome differentiation, which emphasizes the importance of pathological changes of local zang-fu while pursuing the balance between yin and yang in the whole body. Therefore, new and innovative CHM theories of immune balance are urgently required to guide the research on the pharmacodynamic mechanisms through which CHM regulate tumor immunity. Third, most relevant studies focused on the restoratives (e.g., ginseng and astragalus) while fewer studies have explored the roles of CHM for clearing heat and removing toxicity and those for activating blood circulation. One of the principles of CHM in treating malignant tumors is “strengthening vital qi to eliminate pathogenic factors”. Indeed, eliminating pathogenic factors also functions to strengthen vital qi. CHM for eliminating pathogenic factors (including CHM for clearing heat and removing toxicity and those for activating blood circulation) can be used in combinations based on the of the individual patient’s specific condition. Therefore, pharmacological research on antitumor CHM herbs should be further carried out to enrich the database of CHM herbs for tumor immunomodulation. Fourth, most of the currently available research focused on the pharmacodynamic mechanisms of CHM monomers or natural compounds, while few studies have investigated the effects of CHM compound prescriptions on CIC. Therefore, multiomics technologies, such as network pharmacology, botanomics, metabolomics, and bioinformatics, should be used to explore the optimal combinations of CHM targeting multiple steps in CIC so as to further identify new directions in CHM antitumor immunotherapy.

Since its introduction, the concept of CIC has been widely applied in clinical application and basic research. CHM is a critical part of traditional Chinese culture. The value of CHM and their active ingredients and that of CHM compound prescriptions in treating malignant tumors is being increasingly recognized. The intervention of CHM on immune cells and angiogenic cells is a hot research topic at present, but with the continuous development of tumor biology and tumor immunology, tumor-related fibroblasts and extracellular matrix will be a hot research topic in the future. Future research on CIC and CHM pharmacology will further clarify the mechanisms through which CHM regulate tumor immunity. Accordingly, the advantages of CHM in regulating tumor immunity will be additionally recognized, and there will be a broader platform for finding the optimal combinations of CHM herbs for antitumor immunotherapy.

Conclusions

The mechanisms underlying CHM antitumor are complex. On the one hand, CHM (e.g., ginseng and astragalus) can enhance the activity of positive immune cells to improve the body’s anti-tumor immunity. On the other hand, CHM (e.g., tripterygium wilfordii and sophora flavescens) can inhibit the polarization of negative immune cell so as to alleviate the state of immune suppression. TIME includes a variety of immune cells, stromal cells, cytokines and so on. Although the currently available studies have shed light on some antitumor mechanisms, future research is needed to elucidate better the targets (e.g., PD-L1) and mechanisms of CHM regulating CIC. This review clarifies the current progress and creates optimism for CHM’s role in regulating the tumor immunity.

Acknowledgments

Funding: This work was supported by the Foreign Cooperation of Science and Technology Program of Fujian Province (No. 202210034), the School Management Clinical Special Project of Fujian University of Traditional Chinese Medicine (No. XB2022142), and the Outstanding Youth Project in the 900th Hospital of the PLA Joint Logistic Support Force (No. 2021JQ07).

Footnote

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(English Language Editor: J. Gray)