Na Wang
Lu Zhao1,2- 1Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- 2National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
With the constantly deeper understanding of individualized precision therapy, immunotherapy is increasingly developed and personalized. The tumor immune microenvironment (TIME) mainly consists of infiltrating immune cells, neuroendocrine cells, extracellular matrix, lymphatic vessel network, etc. It is the internal environment basis for the survival and development of tumor cells. As a characteristic treatment of traditional Chinese medicine, acupuncture has shown potentially beneficial impacts on TIME. The currently available information demonstrated that acupuncture could regulate the state of immunosuppression through a range of pathways. An effective way to understand the mechanisms of action of acupuncture was to analyze the response following treatment of the immune system. This research reviewed the mechanisms of acupuncture regulating tumor immunological status based on innate and adaptive immunity.
Introduction
The tumor immune microenvironment (TIME) is an important site of interaction between tumors and the human immune system. It mostly consists of tumor cells, immune cells, fibroblasts, endothelial cells, and other cells that provide favorable conditions for tumor proliferation and progression (1). Molecular biology and immunology found that there was a close relationship between the occurrence and development of malignant tumors and the immune microenvironment (2). Natural killer (NK) cells and cytotoxic T cells (CTL), which the immune system uses to eliminate tumor cells and provide the function of immune surveillance (3). Tumor cells secrete a range of immunosuppressive substances to alter the microenvironment as the number of tumor cell mutations increases. As a result, immune cells become polarized into immunosuppressive phenotypes like helper T cell 2 (Th2), regulatory T cell (Treg), bone marrow-derived inhibitory cells, and tumor-associated macrophages. These cells then secrete more immunosuppressive compounds, which allow immune cells to escape and accelerate rapid proliferation (4–6).
Both modern and traditional medicine are faced with the dilemma of actively exploring new ways to improve the survival time of patients with malignant tumors. Since the concept of comprehensive treatment was promoted, acupuncture was used in the traditional treatment methods owing to its unique advantage. Derived from traditional Chinese medicine (TCM), acupuncture has been inherited and carried forward through accumulated practice (7). A variety of needling techniques are used in acupuncture to cause physiological reactions that activate pathways in the peripheral and central nervous systems. Acupuncture typically entails inserting a tiny needle into acupoints and is occasionally used to treat thrusting and/or whirling (8). It features a broad range of capabilities with security and reliability.
Studies demonstrated that acupuncture improved symptoms through systemic conditioning of meridians and acupoints (9). It achieved systemic or local responses by local acupuncture around superficial tumors (10). Additionally, it had a positive therapeutic impact on a range of immunological disorders linked to tumors and could significantly enhance the capacity to fight infections (11). It was worth mentioning that mechanical stimulus activated regional cell processes and neuroreceptors (12). To achieve holistic regulation, it also controlled the release of related biomolecules (peptide hormones, lipid hormones, neuromodulators, neurotransmitters, etc.) (13). The immunomodulatory action of acupuncture was frequently paired with additional benefits (analgesia, antiaging, antistress, etc.), which worked together to strengthen the body’s immunity (14). Modern mechanism research showed that acupuncture took an anti-tumor role in promoting apoptosis of tumor cells, inhibiting proliferation, improving immunosuppression, and strengthening antioxidation (15, 16).
This paper summarized the mechanisms underlying acupuncture-mediated immune regulation from the perspective of innate immunity and adaptive immunity. A better understanding of these mechanisms would provide a scientific basis for the further clinical utilization of acupuncture in the treatment of malignant tumors.
Acupuncture in regulating immune microenvironment
Regulatory effect of acupuncture on innate immunity
As the initial line of body defense, innate immunity is an essential component of the immune system. It is also referred to as nonspecific immunity, which means a type of natural defense that can develop independently of antigen stimulation or develop gradually as a result of long-term ethnic evolution (17). Innate immunity can not only fend off the invasion of pathogenic microbes or toxic substances but also destroy pathogens through phagocytosis and disintegration. Additionally, it significantly influenced the beginning, development, and control of adaptive immunity (18). Studies confirmed that acupuncture had overall and dual regulatory effects on immune cells and molecules of the innate immune system.
Natural killer cells
NK cells are innate lymphocytes that are recognized in various organs (19). They possess typically cytotoxic mechanisms to lyse cancerous or virally infected cells. On the one hand, they directly release lytic granules which majorly consist of granzymes and perforin to induce the death of stressed cells. On the other hand, they also produce multiple tumor necrosis factor (TNF) superfamily members to cause cell apoptosis (20). Previous studies informed that acupuncture regulated NK cells in dual directions. When immunity was low (such as chronic stress and fatigue syndrome), acupuncture increased the number and activity of NK cells, and promoted NK cells to secrete immune factors (such as interferon (IFN)-γ, interleukin (IL)-10, granulocyte-macrophage stimulating factor, etc.) (21, 22). Besides, acupuncture reduced the number of NK cells when relieving pain (23). It activated NK cell receptor CD94 and tyrosine-protein kinase, promoted the expression of cytokines and adhesion factors, and decreased the expression of NK cell inhibitory pathway proteins.
The hypothesis of acupuncture immune enhancement was raised, which considered that acupuncture probably could prevent and kill tumor cells by increasing NK cells (24). In the cyclophosphamide-induced immunosuppressive model, electroacupuncture (EA) could increase the levels of lactate dehydrogenase and acid phosphatase, promote the proliferation of spleen cells induced by concanavalin A and lipopolysaccharide, and increase the killing toxicity of NK cells. Meanwhile, EA could promote the expression of cytokines IL-2, IL-12, TNF-α and IFN-γ, reduce the expression of IL-10, and improve the cyclophosphamide-induced immunosuppression by activating the NF-κB signaling pathway (25). Furthermore, EA combined with cisplatin effectively reduced the tumor volume of patients with stage IIb-IIIb cervical squamous cell carcinoma, and somewhat enhanced the proportion of NK cells in peripheral blood (26). Similarly, further research also demonstrated that EA increased the content of IFN-γ and enhanced the activity of NK cells (27).
Macrophages
Macrophages are the major component of the mononuclear phagocyte system, playing key roles in the innate immune system. They exist various functions and have significant effects on normal homeostasis and disease progression (28). According to the fundamental consensus of the macrophage activation phenotypes, macrophages are defined as pro-inflammatory (M1) and anti-inflammatory (M2) profiles. On the one hand, M1 macrophages have the capacity of starting and sustaining inflammatory responses, secreting pro-inflammatory cytokines, activating endothelial cells, and inducing the recruitment of other immune cells into the inflamed tissue; on the other hand, M2 macrophages promote the resolution of inflammation, phagocytose apoptotic cells, drive collagen deposition, coordinate tissue integrity, and release anti-inflammatory mediators (29). The disproportion of M1/M2 induced tumorigenesis and development, immune escape, subsequent metastasis, and drug resistance (30).
Regulating the phagocytic ability of macrophages and the secretion of immune factors were important cellular mechanisms for acupuncture to enhance immunity and treat diverse diseases. Acupuncture promoted the macrophage phenotype and IL-10 expression to mitigate the pain and inflammation of animal muscle. Further study demonstrated that acupuncture modified the macrophage phenotype of inflammatory muscle, and it could be the basic process causing the IL-10-induced analgesic and anti-inflammatory actions (31). In addition, EA was an adjuvant therapy for spinal cord injury based on decreasing the proportion of M1 macrophages, TNF-α, and IL-6 levels while enhancing the proportion of M2 macrophages, IL-10, and neurotrophin-3 (NT-3) expression (32). Tumor-associated macrophages play an important role in the functional composition of TIME, which usually stimulates proliferation, immunosuppression, and angiogenesis to promote tumor growth and metastasis (33). Therefore, the development of an antineoplastic method targeting macrophage polarization is also the focus of the current treatment.
Mast cells
Mast cell (MC) is a group of bone marrow-derived immune cells that differentiates and matures in peripheral tissues. MC plays an immunomodulatory role in both innate and acquired immune responses, thus affecting the progression and prognosis of related diseases (34). The infiltration of MC in TIME was closely related to the prognosis of malignant tumors (35). Previous studies confirmed that MC aggregated around tumors. It played a tumor-promoting or anti-tumor role in different types of tumors or in different processes of the same tumor, which affected tumor growth and metastasis mainly by affecting tumor angiogenesis, participating in immune regulation, and promoting tissue remodeling (36). There were many reports on the regulation of MC in acupuncture. MC aggregated in small blood vessels, nerves, and nerve endings of humans and rats along the meridian (37). Acupuncture stimulation could increase the aggregation and degranulation effect of MC. Histamine produced by the degranulation of MC acted on blood vessels and triggered meridian sensing (38). Besides, acupuncture regulated the function of MC in both directions and it alleviated the abnormal degranulation of MC under pathological conditions (39). Acupuncture relieved MC degranulation and promoted synaptic-like function, which was an important immune mechanism for the treatment of allergic diseases and inflammatory diseases (40).
Microglia
Microglia is an important type of innate immune cell in the central nervous system, which is the main effector in the process of inflammation progression (41). Acupuncture was used to treat neurodegenerative disorders, central traumatic diseases, and neuropathic pain by regulating the microglia (42–44), which was widely involved in a variety of pathological processes. Increasing evidence suggested that microglial activation was critical for neurogenesis, angiogenesis, and synaptic remodeling. It could move to the site before tumor metastasis, induce local and systemic immunosuppression, promote tumor angiogenesis, reorganize surrounding tissue, promote matrix remodeling and tumor invasion, and take a vital part in tumor brain metastasis (45–47). The mechanism of chemotherapy-induced peripheral neuropathy was considered as persistent activation of spinal cord microglia through strengthening TREM/DAP12 signaling (48). On the contrary, the therapeutic mechanism of action of paclitaxel-induced pain hypersensitivities has been confirmed that EA effectively and persistently suppressed TLR4 signaling and TRPV1 upregulation in DRG neurons, which further resulted in reduced spinal glia activation (49). Furthermore, it was mutually corroborative that the feasible mechanism was associated with the inhibition of the activated TLR4/NF-κB signaling pathway (50).
Other innate immune cells
Neutrophils, which originate from myeloid precursors, are crucial components of white blood cells and the first responders of the innate immune system against extracellular pathogens and wound healing (51). Recent studies demonstrated that neutrophils were widely involved in the occurrence, development, migration and invasion of tumors (52), and neutrophils with different phenotypes played a significant part in the formation of tumor immunosuppressive microenvironment (53). In the process of innate immunity, neutrophils are gathered and activated at the inflammatory site. They activated signal transduction pathways by releasing inflammation-related factors such as reactive oxygen species (ROS) and cytokines, which formed a series of cascade reactions to regulate inflammation and immunity (54, 55). Acupuncture bidirectionally regulated neutrophils. It increased the number and activity of neutrophils when inflammatory reactions occurred (56), while it down-regulated the number and activation rate of neutrophils in stressful conditions or allergic diseases to counteract stress damage (57).
Dendritic cell (DC) is a rare group of immune cells in tumor tissues, which regulates immune signals by ingesting and presenting antigens to T cells, contacting directly between cells, and providing cytokines (58). The regulation of DC function is significantly influenced by environmental factors. The initiation of antigen-characteristic immunity and tolerance can be regulated by cell surface and intracellular cytokine receptors, pathogen-related molecular models and injury-related molecular models (59). As an important antigen-presenting cell, DC is commonly in a state of immunosuppression or immune tolerance in TIME. The role of different DC cell subsets and their immunomodulatory mechanism is of great significance for clinical treatment. Conventional DC (cDC) 1 induced the anti-tumor immune response of killer T cells and improved the survival rate of cancer patients, while cDC2 induced the anti-tumor immune function of CD4+ T cells (60). Under the intervention of acupuncture, DC tends to gather at the acupoint after activation from the surrounding tissue. It is speculated that the related mechanism may be caused by the neurogenic response of the skin around the acupoint after acupuncture stimulation (61, 62). The research on the relationship between acupuncture and DC is still in the stage of exploration and development, which needs to be supported by further research data.
Regulatory effect of acupuncture on adaptive immune cells
Adaptive immunity includes T-cell-mediated cellular immunity and B-cell-mediated humoral immunity. The main force involved in anti-tumor adaptive immunity is T lymphocytes, which mainly include CTL and Treg cells (63). As the main member of anti-tumor immunity, CTL can recognize the antigen complex on the surface of tumor cells and secrete granzyme and perforin to clear tumor cells. However, under the tumor background, immunosuppressive cytokines (such as IL-10, IL-4, CX3CL, etc.) and negative costimulatory molecules (such as PD-1/PD-L1, CTLA-4/CD80/CD86, etc.) greatly limit the proliferation and activity of CTL and even cooperate with tumor extracellular matrix to exclude CTL from the tumor parenchyma, making it unable to contact tumor cells (64, 65). Treg cells can produce immunosuppressive cytokines (such as TGF-β and IL-10) and CTLA-4, which hinder the activation and expansion of CTL (66, 67).
Acupuncture on cellular immunity
Cellular immunity is the main immune response in human autoimmune mechanisms. The immune function of patients with malignant tumors is related to the imbalance of the proportion and quantity of T cells. The T-cell-mediated immune response is characterized by the presence of an inflammatory response dominated by monocyte infiltration and/or specific cytotoxicity. Acupuncture has been confirmed that regulated the differentiation of T-cell subsets and promoted the drift of Th1/Th2 and Th17/Treg toward Th2 and Treg, respectively (68). Thus, it led to a reduction in pro-inflammatory factors (such as IL-2, IL-12, and IFN-γ) and an increase in the expression of IL-10. It decreased serum antibodies and nitric oxide and also affected the levels of inflammatory signaling molecules (such as ERK, NF-κB, AP-1, p38, etc.) (69). This modulation of T cell subsets and their associated inflammatory response factors was considered an important cellular immune mechanism for acupuncture in the treatment of allergic diseases and nonspecific inflammatory diseases (70–73). Besides, acupuncture regulated the expression of FAS/FAS-L in the thymus, increased the apoptosis rate of T cells in peripheral blood and mediated T cell tolerance, which had therapeutic effects on rheumatoid arthritis (74).
As for the treatment of cancer-related diseases, the absolute account of T cell subsets and anti-tumor response were closely related to the prognosis of tumor patients. Preclinical studies demonstrated that more CD4+ and CD8+ cells were likely responsible for the extended survival time and successful treatment of tumors (75–77). Additionally, in rat models with bone cancer pain, EA reduced mechanical allodynia even though its analgesic effectiveness was inferior to morphine. Contrary to morphine, the T cell proliferation, plasma IL-2 level, as well as the proportions of CD3+CD4+ and CD3+CD8+ T cells in the EA group were significantly increased (78). The analgesic and immunomodulatory effects of EA may have the same mechanism through an opioid-mediated pathway and need to be further investigated. In patients with gastric cancer, acupuncture compound general anesthesia reduced the negative impacts on immune function based on obviously decreased levels of CD3+, CD4+ and CD4+/CD8+ after subtotal gastrectomy (79). Similarly, in patients following gastrointestinal tumor resection, EA compound general anesthesia had a satisfactory anesthetic effect and immunomodulatory function, which had lower levels of TNF-α, IL-6, and IL-1β and decreased levels of CD3+, CD4+ and CD4+/CD8+ (80). As for cancer-related fatigue, acupuncture was beneficial to improve the symptoms of fatigue and promote the absolute counts of CD3+, CD4+, CD8+ and CD4+/CD8+ (81). Saam acupuncture was consistent with the above outcomes that had a statistical expression in CD3+, CD8+ and T-cell subsets (82). In conclusion, acupuncture is capable of effectively increasing the level of T cells in TIME, especially the absolute number of cytotoxic T cell subsets, which is an important tool to enhance the effectiveness of tumor immunotherapy.
Acupuncture on humoral immunity
The proliferation, differentiation and antibody secretion of B cells are the basic processes of humoral immunity. Acupuncture was demonstrated that had a dual regulatory effect on the production of antibodies by B cells (83). When immune intolerance occurs in the organism, antibodies are frequently found in the serum of overexpression. Acupuncture could reduce the content of serum immunoglobulins (IgG, IgA, IgM) in allergic diseases and non-inflammatory diseases (84–86). Conversely, it could increase the production of IgG and IgM when the humoral immune response was insufficient. During surgery, EA seemed to lessen the immunosuppression of both the humoral and cellular components. When comparing immunoglobulin levels postoperatively, the IgA levels were significantly higher in the EA group compared to the pure-drug group. Under the same circumstances as general anesthetic alone, needles combination anesthesia partially attenuated perioperative immunosuppression (87). In addition, acupuncture had indirect regulatory effects on humoral immunity by affecting antigen-presenting cells, the release of immune factors and the generation of complement.
Outlook and summary
Malignant tumors produce or secrete some immunosuppressive substances to evade the role of the immune system, to expect the normal growth and proliferation of tumor cells (88). Acupuncture has a sufficiently dual regulating effect and can improve immune function. The mechanism of tumor elimination by restoring the body’s immune ability is consistent with the concept of “nourishing positive accumulation and eliminating cancer by itself” in TCM (89). The formation and dynamic changes in TIME involve many different types of cells and multiple signaling pathways, which are similar to the multitarget and bidirectional regulation of immunity in TCM (90).
Discussing the relationship and mutual influence of acupuncture on TIME are current research hotspots, but the accuracy, depth and breadth of the research are not enough. From the retrieved literature, most of the mechanism studies were still focused on the mechanism of immune function. Moreover, the research was still based on the dose-effect study of acupuncture on the tumor, and there was little discussion on the internal mechanism and pathway of the tumor. Therefore, the content of this article is both logical and speculative. Future research should explore the mechanism of acupuncture on TIME more deeply from the aspects of signal pathway with modern biology and technology. This will better provide a theoretical basis and standardized treatment for clinical treatment.
Author contributions
All authors contributed to the study’s conception and design. Material preparation, paper collection and analysis were performed by FK and NW. The first draft of the manuscript was written by NW and all authors commented on previous versions of the manuscript. All authors contributed to the article and approved the submitted version.
Funding
This work was supported by grants from the National Natural Science Foundation of China (No. 81403220), the National Key Research and Development (R&D) Plan (No.2018YFC1707400), and the Tianjin Health and Family Planning-high Level Talent Selection and Training Project.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
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References
1. Locy H, de Mey S, de Mey W, De Ridder M, Thielemans K, Maenhout SK. Immunomodulation of the tumor microenvironment: Turn foe into friend. Front Immunol (2018) 9:2909. doi: 10.3389/fimmu.2018.02909
2. Darvin P, Toor SM, Sasidharan Nair V, Elkord E. Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp Mol Med (2018) 50(12):1–11. doi: 10.1038/s12276-018-0191-1
3. Church SE, Galon J. Regulation of CTL infiltration within the tumor microenvironment. Adv Exp Med Biol (2017) 1036:33–49. doi: 10.1007/978-3-319-67577-0_3
4. Hinshaw DC, Shevde LA. The tumor microenvironment innately modulates cancer progression. Cancer Res (2019) 79(18):4557–66. doi: 10.1158/0008-5472.Can-18-3962
5. Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol (2013) 14(10):1014–22. doi: 10.1038/ni.2703
6. Duan Q, Zhang H, Zheng J, Zhang L. Turning cold into hot: Firing up the tumor microenvironment. Trends Cancer (2020) 6(7):605–18. doi: 10.1016/j.trecan.2020.02.022
7. Han JS, Ho YS. Global trends and performances of acupuncture research. Neurosci Biobehav Rev (2011) 35(3):680–7. doi: 10.1016/j.neubiorev.2010.08.006
8. Lee YS, Jung WM, Lee IS, Lee H, Park HJ, Chae Y. Visualizing motion patterns in acupuncture manipulation. J visualized experiments JoVE (2016) 113:e54213. doi: 10.3791/54213
9. Cheng CS, Chen LY, Ning ZY, Zhang CY, Chen H, Chen Z, et al. Acupuncture for cancer-related fatigue in lung cancer patients: A randomized, double-blind, placebo-controlled pilot trial. Supportive Care Cancer Off J Multinational Assoc Supportive Care Cancer (2017) 25(12):3807–14. doi: 10.1007/s00520-017-3812-7
10. Li S, Zhao S, Guo Y, Yang Y, Huang J, Wang J, et al. Clinical efficacy and potential mechanisms of acupoint stimulation combined with chemotherapy in combating cancer: A review and prospects. Front Oncol (2022) 12:864046. doi: 10.3389/fonc.2022.864046
11. Li N, Guo Y, Gong Y, Zhang Y, Fan W, Yao K, et al. The anti-inflammatory actions and mechanisms of acupuncture from acupoint to target organs via neuro-immune regulation. J Inflammation Res (2021) 14:7191–224. doi: 10.2147/jir.S341581
12. Witt CM. Clinical research on acupuncture - concepts and guidance on efficacy and effectiveness research. Chin J Integr Med (2011) 17(3):166–72. doi: 10.1007/s11655-011-0662-x
13. Cai Y, Shen J, Zhong D, Li Y, Wu T. Status quo, issues, and challenges for acupuncture research evidence: an overview of clinical and fundamental studies. J Evidence-Based Med (2012) 5(1):12–24. doi: 10.1111/j.1756-5391.2012.01163.x
14. Zeng BY, Zhao K, Liang FR. Acupuncture is a fundamental part of traditional Chinese medicine. preface. Int Rev Neurobiol (2013) 111:xv–xviii. doi: 10.1016/b978-0-12-411545-3.09989-2
15. Han QQ, Fu Y, Le JM, Ma YJ, Wei XD, Ji HL, et al. The therapeutic effects of acupuncture and electroacupuncture on cancer-related symptoms and side-effects. J Cancer (2021) 12(23):7003–9. doi: 10.7150/jca.55803
16. Oura M, Omata F, Nishikawa Y. Acupuncture for cancer survivors. JAMA Oncol (2021) 7(9):1399–400. doi: 10.1001/jamaoncol.2021.2517
17. Demaria O, Cornen S, Daëron M, Morel Y, Medzhitov R, Vivier E. Harnessing innate immunity in cancer therapy. Nature (2019) 574(7776):45–56. doi: 10.1038/s41586-019-1593-5
18. Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ. Natural innate and adaptive immunity to cancer. Annu Rev Immunol (2011) 29:235–71. doi: 10.1146/annurev-immunol-031210-101324
19. Wu SY, Fu T, Jiang YZ, Shao ZM. Natural killer cells in cancer biology and therapy. Mol Cancer (2020) 19(1):120. doi: 10.1186/s12943-020-01238-x
20. Prager I, Watzl C. Mechanisms of natural killer cell-mediated cellular cytotoxicity. J leukocyte Biol (2019) 105(6):1319–29. doi: 10.1002/jlb.Mr0718-269r
21. Lee SW, Liong ML, Yuen KH, Krieger JN. Acupuncture and immune function in chronic prostatitis/chronic pelvic pain syndrome: A randomized, controlled study. Complementary therapies Med (2014) 22(6):965–9. doi: 10.1016/j.ctim.2014.10.010
22. Li G, Li S, An L, Wang B. Electroacupuncture alleviates intraoperative immunosuppression in patients undergoing supratentorial craniotomy. Acupuncture Med J Br Med Acupuncture Soc (2013) 31(1):51–6. doi: 10.1136/acupmed-2012-010254
23. Mori H, Kuge H, Tanaka TH, Taniwaki E, Hanyu K, Morisawa T. Effects of acupuncture treatment on natural killer cell activity, pulse rate, and pain reduction for older adults: An uncontrolled, observational study. J Integr Med (2013) 11(2):101–5. doi: 10.3736/jintegrmed2013012
24. Johnston MF, Ortiz Sánchez E, Vujanovic NL, Li W. Acupuncture may stimulate anticancer immunity via activation of natural killer cells. Evidence-Based complementary Altern Med eCAM (2011) 2011:481625. doi: 10.1093/ecam/nep236
25. Huang Z, Hu Z, Ouyang J, Huang C. Electroacupuncture regulates the DREAM/NF-κB signalling pathway and ameliorates cyclophosphamide-induced immunosuppression in mice. Acupuncture Med J Br Med Acupuncture Soc (2019) 37(5):292–300. doi: 10.1136/acupmed-2017-011593
26. Saraswati W, Dahlan EG, Saputra K, Sutrisno TC. Effect of electroacupuncture on natural-killer cells and tumor size in patients with cervical squamous-cell carcinoma: A randomized controlled trial. Med acupuncture (2019) 31(1):29–36. doi: 10.1089/acu.2018.1316
27. Yang G, Zheng B, Yu Y, Huang J, Zhu H, Deng D, et al. Electroacupuncture at zusanli (ST36), guanyuan (CV4), and qihai (CV6) acupoints regulates immune function in patients with sepsis via the PD-1 pathway. BioMed Res Int (2022) 2022:7037497. doi: 10.1155/2022/7037497
28. Locati M, Curtale G, Mantovani A. Diversity, mechanisms, and significance of macrophage plasticity. Annu Rev Pathol (2020) 15:123–47. doi: 10.1146/annurev-pathmechdis-012418-012718
29. Viola A, Munari F, Sánchez-Rodríguez R, Scolaro T, Castegna A. The metabolic signature of macrophage responses. Front Immunol (2019) 10:1462. doi: 10.3389/fimmu.2019.01462
30. Wu K, Lin K, Li X, Yuan X, Xu P, Ni P, et al. Redefining tumor-associated macrophage subpopulations and functions in the tumor microenvironment. Front Immunol (2020) 11:1731. doi: 10.3389/fimmu.2020.01731
31. da Silva MD, Bobinski F, Sato KL, Kolker SJ, Sluka KA, Santos AR. IL-10 cytokine released from M2 macrophages is crucial for analgesic and anti-inflammatory effects of acupuncture in a model of inflammatory muscle pain. Mol Neurobiol (2015) 51(1):19–31. doi: 10.1007/s12035-014-8790-x
32. Zhao J, Wang L, Li Y. Electroacupuncture alleviates the inflammatory response via effects on M1 and M2 macrophages after spinal cord injury. Acupuncture Med J Br Med Acupuncture Soc (2017) 35(3):224–30. doi: 10.1136/acupmed-2016-011107
33. Ngambenjawong C, Gustafson HH, Pun SH. Progress in tumor-associated macrophage (TAM)-targeted therapeutics. Advanced Drug delivery Rev (2017) 114:206–21. doi: 10.1016/j.addr.2017.04.010
34. Lichterman JN, Reddy SM. Mast cells: A new frontier for cancer immunotherapy. Cells (2021) 10(6):1270. doi: 10.3390/cells10061270
35. Komi DEA, Redegeld FA. Role of mast cells in shaping the tumor microenvironment. Clin Rev Allergy Immunol (2020) 58(3):313–25. doi: 10.1007/s12016-019-08753-w
36. Albini A, Bruno A, Noonan DM, Mortara L. Contribution to tumor angiogenesis from innate immune cells within the tumor microenvironment: Implications for immunotherapy. Front Immunol (2018) 9:527. doi: 10.3389/fimmu.2018.00527
37. Zhang D, Ding G, Shen X, Yao W, Zhang Z, Zhang Y, et al. Role of mast cells in acupuncture effect: A pilot study. Explore (New York NY) (2008) 4(3):170–7. doi: 10.1016/j.explore.2008.02.002
38. Ding N, Jiang J, Qin P, Wang Q, Hu J, Li Z. Mast cells are important regulator of acupoint sensitization via the secretion of tryptase, 5-hydroxytryptamine, and histamine. PloS One (2018) 13(3):e0194022. doi: 10.1371/journal.pone.0194022
39. Wang Z, Yi T, Long M, Ding F, Ouyang L, Chen Z. Involvement of the negative feedback of IL-33 signaling in the anti-inflammatory effect of electro-acupuncture on allergic contact dermatitis via targeting MicroRNA-155 in mast cells. Inflammation (2018) 41(3):859–69. doi: 10.1007/s10753-018-0740-8
40. Dou B, Li Y, Ma J, Xu Z, Fan W, Tian L, et al. Role of neuroimmune crosstalk in mediating the anti-inflammatory and analgesic effects of acupuncture on inflammatory pain. Front Neurosci (2021) 15:695670. doi: 10.3389/fnins.2021.695670
41. Rodríguez-Gómez JA, Kavanagh E, Engskog-Vlachos P, Engskog MKR, Herrera AJ, Espinosa-Oliva AM, et al. Microglia: Agents of the CNS pro-inflammatory response. Cells (2020) 9(7):1717. doi: 10.3390/cells9071717
42. Cao BQ, Tan F, Zhan J, Lai PH. Mechanism underlying treatment of ischemic stroke using acupuncture: Transmission and regulation. Neural regeneration Res (2021) 16(5):944–54. doi: 10.4103/1673-5374.297061
43. Ali U, Apryani E, Wu HY, Mao XF, Liu H, Wang YX. Low frequency electroacupuncture alleviates neuropathic pain by activation of spinal microglial IL-10/β-endorphin pathway. Biomedicine pharmacotherapy = Biomedecine pharmacotherapie (2020) 125:109898. doi: 10.1016/j.biopha.2020.109898
44. Li L, Li L, Zhang J, Huang S, Liu W, Wang Z, et al. Disease stage-associated alterations in learning and memory through the electroacupuncture modulation of the cortical microglial M1/M2 polarization in mice with alzheimer's disease. Neural plasticity (2020) 2020:8836173. doi: 10.1155/2020/8836173
45. Borst K, Dumas AA, Prinz M. Microglia: Immune and non-immune functions. Immunity (2021) 54(10):2194–208. doi: 10.1016/j.immuni.2021.09.014
46. Prinz M, Jung S, Priller J. Microglia biology: One century of evolving concepts. Cell (2019) 179(2):292–311. doi: 10.1016/j.cell.2019.08.053
47. Colonna M, Butovsky O. Microglia function in the central nervous system during health and neurodegeneration. Annu Rev Immunol (2017) 35:441–68. doi: 10.1146/annurev-immunol-051116-052358
48. Hu LY, Zhou Y, Cui WQ, Hu XM, Du LX, Mi WL, et al. Triggering receptor expressed on myeloid cells 2 (TREM2) dependent microglial activation promotes cisplatin-induced peripheral neuropathy in mice. Brain behavior Immun (2018) 68:132–45. doi: 10.1016/j.bbi.2017.10.011
49. Li Y, Yin C, Li X, Liu B, Wang J, Zheng X, et al. Electroacupuncture alleviates paclitaxel-induced peripheral neuropathic pain in rats via suppressing TLR4 signaling and TRPV1 upregulation in sensory neurons. Int J Mol Sci (2019) 20(23):5917. doi: 10.3390/ijms20235917
50. Zhao YX, Yao MJ, Liu Q, Xin JJ, Gao JH, Yu XC. Electroacupuncture treatment attenuates paclitaxel-induced neuropathic pain in rats via inhibiting spinal glia and the TLR4/NF-κB pathway. J Pain Res (2020) 13:239–50. doi: 10.2147/jpr.S241101
51. Ocana A, Nieto-Jiménez C, Pandiella A, Templeton AJ. Neutrophils in cancer: prognostic role and therapeutic strategies. Mol Cancer (2017) 16(1):137. doi: 10.1186/s12943-017-0707-7
52. Shaul ME, Fridlender ZG. Tumour-associated neutrophils in patients with cancer. Nat Rev Clin Oncol (2019) 16(10):601–20. doi: 10.1038/s41571-019-0222-4
53. Hajizadeh F, Aghebati Maleki L, Alexander M, Mikhailova MV, Masjedi A, Ahmadpour M, et al. Tumor-associated neutrophils as new players in immunosuppressive process of the tumor microenvironment in breast cancer. Life Sci (2021) 264:118699. doi: 10.1016/j.lfs.2020.118699
54. Li S, Cong X, Gao H, Lan X, Li Z, Wang W, et al. Tumor-associated neutrophils induce EMT by IL-17a to promote migration and invasion in gastric cancer cells. J Exp Clin Cancer Res CR (2019) 38(1):6. doi: 10.1186/s13046-018-1003-0
55. Giese MA, Hind LE, Huttenlocher A. Neutrophil plasticity in the tumor microenvironment. Blood (2019) 133(20):2159–67. doi: 10.1182/blood-2018-11-844548
56. Lu W, Matulonis UA, Doherty-Gilman A, Lee H, Dean-Clower E, Rosulek A, et al. Acupuncture for chemotherapy-induced neutropenia in patients with gynecologic malignancies: A pilot randomized, sham-controlled clinical trial. J Altern complementary Med (New York NY) (2009) 15(7):745–53. doi: 10.1089/acm.2008.0589
57. Arranz L, Guayerbas N, Siboni L, de la Fuente M. Effect of acupuncture treatment on the immune function impairment found in anxious women. Am J Chin Med (2007) 35(1):35–51. doi: 10.1142/s0192415x07004606
58. Gardner A, de Mingo Pulido Á, Ruffell B. Dendritic cells and their role in immunotherapy. Front Immunol (2020) 11:924. doi: 10.3389/fimmu.2020.00924
59. Patente TA, Pinho MP, Oliveira AA, Evangelista GCM, Bergami-Santos PC, Barbuto JAM. Human dendritic cells: Their heterogeneity and clinical application potential in cancer immunotherapy. Front Immunol (2018) 9:3176. doi: 10.3389/fimmu.2018.03176
60. Lee YS, Radford KJ. The role of dendritic cells in cancer. Int Rev Cell Mol Biol (2019) 348:123–78. doi: 10.1016/bs.ircmb.2019.07.006
61. Dong H, Zhong Z, Chen W, Wu X, Zhang Q, Huang G, et al. Effect of acupuncture on endometrial angiogenesis and uterus dendritic cells in COH rats during peri-implantation period. Evidence-Based complementary Altern Med eCAM (2017) 2017:3647080. doi: 10.1155/2017/3647080
62. Kan BH, Yu JC, Zhao L, Zhao J, Li Z, Suo YR, et al. Acupuncture improves dendritic structure and spatial learning and memory ability of alzheimer's disease mice. Neural regeneration Res (2018) 13(8):1390–5. doi: 10.4103/1673-5374.235292
63. Wu D. Innate and adaptive immune cell metabolism in tumor microenvironment. Adv Exp Med Biol (2017) 1011:211–23. doi: 10.1007/978-94-024-1170-6_7
64. Deets KA, Vance RE. Inflammasomes and adaptive immune responses. Nat Immunol (2021) 22(4):412–22. doi: 10.1038/s41590-021-00869-6
65. Pan P, Ma Z, Zhang Z, Ling Z, Wang Y, Liu Q, et al. Acupuncture can regulate the peripheral immune cell spectrum and inflammatory environment of the vascular dementia rat, and improve the cognitive dysfunction of the rats. Front Aging Neurosci (2021) 13:706834. doi: 10.3389/fnagi.2021.706834
66. Li LJ, Shi YC, Luo MX, Zhao CL. Effects of moxibustion on treg cells in sarcoma microenvironment. J Integr Med (2021) 19(3):251–7. doi: 10.1016/j.joim.2021.02.001
67. Jin L, Han C. Effects of acupuncture on clinical outcome and helper T cell distribution and abundance in patients with convalescent ischemic stroke. Am J Trans Res (2021) 13(7):8118–25.
68. Wei Y, Dong M, Zhang H, Lv Y, Liu J, Wei K, et al. Acupuncture attenuated inflammation and inhibited Th17 and treg activity in experimental asthma. Evidence-Based complementary Altern Med eCAM (2015) 2015:340126. doi: 10.1155/2015/340126
69. Liu Z, Jiao Y, Yu T, Wang H, Zhang Y, Liu D, et al. A review on the immunomodulatory mechanism of acupuncture in the treatment of inflammatory bowel disease. Evidence-Based complementary Altern Med eCAM (2022) 2022:8528938. doi: 10.1155/2022/8528938
70. Hwang JH, Jung HW, Kang SY, Kang AN, Ma JN, Meng XL, et al. Therapeutic effects of acupuncture with MOK, a polyherbal medicine, on PTU-induced hypothyroidism in rats. Exp Ther Med (2018) 16(1):310–20. doi: 10.3892/etm.2018.6190
71. Pei L, Geng H, Guo J, Yang G, Wang L, Shen R, et al. Effect of acupuncture in patients with irritable bowel syndrome: A randomized controlled trial. Mayo Clin Proc (2020) 95(8):1671–83. doi: 10.1016/j.mayocp.2020.01.042
72. Tang W, Dong M, Teng F, Cui J, Zhu X, Wang W, et al. TMT-based quantitative proteomics reveals suppression of SLC3A2 and ATP1A3 expression contributes to the inhibitory role of acupuncture on airway inflammation in an OVA-induced mouse asthma model. Biomedicine pharmacotherapy = Biomedecine pharmacotherapie (2021) 134:111001. doi: 10.1016/j.biopha.2020.111001
73. Yang YQ, Chen HP, Wang Y, Yin LM, Xu YD, Ran J. Considerations for use of acupuncture as supplemental therapy for patients with allergic asthma. Clin Rev Allergy Immunol (2013) 44(3):254–61. doi: 10.1007/s12016-012-8321-3
74. Xu Y, Hong S, Zhao X, Wang S, Xu Z, Ding S, et al. Acupuncture alleviates rheumatoid arthritis by immune-network modulation. Am J Chin Med (2018) 46(5):997–1019. doi: 10.1142/s0192415x18500520
75. Liu A, Xia Y, Li W, Zhang G, Liu Y, Ye S, et al. The predictive value of changes in the absolute counts of peripheral lymphocyte subsets for progression and prognosis in breast cancer patients. Contrast media Mol Imaging (2022) 2022:3444360. doi: 10.1155/2022/3444360
76. Chen HY, Li SG, Cho WC, Zhang ZJ. The role of acupoint stimulation as an adjunct therapy for lung cancer: A systematic review and meta-analysis. BMC complementary Altern Med (2013) 13:362. doi: 10.1186/1472-6882-13-362
77. Zhang Z, Yu Q, Zhang X, Wang X, Su Y, He W, et al. Electroacupuncture regulates inflammatory cytokines by activating the vagus nerve to enhance antitumor immunity in mice with breast tumors. Life Sci (2021) 272:119259. doi: 10.1016/j.lfs.2021.119259
78. Liang Y, Du JY, Fang JF, Fang RY, Zhou J, Shao XM, et al. Alleviating mechanical allodynia and modulating cellular immunity contribute to electroacupuncture's dual effect on bone cancer pain. Integr Cancer Ther (2018) 17(2):401–10. doi: 10.1177/1534735417728335
79. Wang N, Ou Y, Qing W. Combined acupuncture and general anesthesia on immune and cognitive function in elderly patients following subtotal gastrectomy for gastric cancer. Oncol Lett (2018) 15(1):189–94. doi: 10.3892/ol.2017.7262
80. Xu J, Li P, Zheng L, Chen Q. Effect observation of electro-acupuncture anesthesia combined with general anesthesia in elderly patients undergoing gastrointestinal tumor resection. Front Surg (2022) 9:901638. doi: 10.3389/fsurg.2022.901638
81. Yang G, Hu RY, Deng AJ, Huang Y, Li J. Effects of electro-acupuncture at zusanli, guanyuan for sepsis patients and its mechanism through immune regulation. Chin J Integr Med (2016) 22(3):219–24. doi: 10.1007/s11655-016-2462-9
82. Kim DJ, Park SH, Seo JC, Kim KS, Sohn KC, Shin IH, et al. Efficacy of saam acupuncture treatment on improvement of immune cell numbers in cancer patients: a pilot study. J traditional Chin Med = Chung i tsa chih ying wen pan (2014) 34(5):550–4. doi: 10.1016/s0254-6272(15)30061-3
83. Ding SS, Hong SH, Wang C, Guo Y, Wang ZK, Xu Y. Acupuncture modulates the neuro-endocrine-immune network. QJM monthly J Assoc Physicians (2014) 107(5):341–5. doi: 10.1093/qjmed/hct196
84. Liu X, Sun L, Xiao J, Yin S, Liu C, Li Q, et al. Effect of acupuncture and point-injection treatment on immunologic function in rheumatoid arthritis. J traditional Chin Med = Chung i tsa chih ying wen pan (1993) 13(3):174–8.
85. Cabioglu MT, Ergene N, Surucu HS, Celik HH, Findik D. Serum IgG, IgA, IgM, and IgE levels after electroacupuncture and diet therapy in obese women. Am J Chin Med (2007) 35(6):955–65. doi: 10.1142/s0192415x07005429
86. Yim YK, Lee H, Hong KE, Kim YI, Lee BR, Son CG, et al. Electro-acupuncture at acupoint ST36 reduces inflammation and regulates immune activity in collagen-induced arthritic mice. Evidence-Based complementary Altern Med eCAM (2007) 4(1):51–7. doi: 10.1093/ecam/nel054
87. Li G, Li S, Wang B, An L. The effect of electroacupuncture on postoperative immunoinflammatory response in patients undergoing supratentorial craniotomy. Exp Ther Med (2013) 6(3):699–702. doi: 10.3892/etm.2013.1225
88. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Sci (New York NY) (2011) 331(6024):1565–70. doi: 10.1126/science.1203486
89. Zhang Y, Lou Y, Wang J, Yu C, Shen W. Research status and molecular mechanism of the traditional Chinese medicine and antitumor therapy combined strategy based on tumor microenvironment. Front Immunol (2020) 11:609705. doi: 10.3389/fimmu.2020.609705
Keywords: acupuncture, tumor immune microenvironment, traditional Chinese medicine, immunotherapy, cancer immunity
Citation: Wang N, Zhao L, Zhang D and Kong F (2023) Research progress on the immunomodulatory mechanism of acupuncture in tumor immune microenvironment. Front. Immunol. 14:1092402. doi: 10.3389/fimmu.2023.1092402
Received: 08 November 2022; Accepted: 03 February 2023;
Published: 14 February 2023.
Edited by:
Giovanni Rosti, San Matteo Hospital Foundation (IRCCS), ItalyReviewed by:
Wenzheng Jiang, East China Normal University, ChinaO Sang Kwon, Wonkwang University, Republic of Korea
Copyright © 2023 Wang, Zhao, Zhang and Kong. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Fanming Kong, kongfanming08@163.com