Traditional Chinese Medicine in Regulating Tumor Microenvironment

Figures & data

Table 1 Mechanisms of Action of Immune Cells

Immune Cells	Mechanism of Action
NKs^Citation12,Citation13	Secreting perforin and granzyme to destroy cancer cells; Secreting cytokines such as IFN- γ and TNF- α to maintain the pro-inflammatory phenotype of TAMs and TANs.
Macrophages^Citation14,Citation15	M1 macrophages phagocytose and destroy cancer cells by releasing large amounts of pro-inflammatory substances; M2 macrophages produce the cytokines to promote vascular development; TAMs prevent T cell recruitment and activation by releasing cytokines and chemokines, immunosuppression, and chronic inflammation.
DCs^Citation16–18	Mature DCs have a strong antigen-presenting capacity and the ability to stimulate B cells and T cells; DCs express IDO, leading to T cell cycle arrest or apoptosis and inducing Treg cell differentiation.
MDSCs^Citation19–22	NOS2 can promote the inhibitory activity of M-MDSCs, and the tumor can rapidly differentiate into TAMs due to the increased hypoxia.
TAN^Citation23–26	TANs-N1 release large amounts of cellular hydrolases that produce ROS, MPO, and other reactive oxides to destroy tumor cells; TANs-N1 also triggers the IL-18 activation and the IFN-β secretion, which activates NKs, DCs, macrophages, and other immune cells; TANs-N2 produce ROS, cytokines, proteases, MMP-9 to promote the proliferation and metastasis of tumor cells.
T lymphocytes^Citation26–33	CD4+T cells recruit CD8+T cells and promote their proliferation; CD4+T cells secretes IFN-γ-dependent chemokines and IL-2 to enhance the effector function of CD8+ T cells; CD8+ T cells destroy target cells through granzyme- and perforin-mediated apoptosis or Fas/Fasl-mediated cell death; Tregs reduced NK cells, promoted the depletion of effector T cells and inhibited the cytotoxic effect of effector T cells through the production of GF-β, IL-10 and IL-35; Th1 cells can enhance the killing ability of T cells and activate macrophages; Th2 cells can assist B lymphocytes to produce specific antigens to perform anti-tumor function.
B lymphocytes^Citation34–36	TIL-Bs have a strong antitumor response in TME; Regulatory B cells secrete IL-10 or TGF-β to impair anti-tumor immunity and converse resting CD4+ T cells to Tregs.

Figure 1 Crosstalk between cancer cells and TME cells. T lymphocytes mainly include CD4+ T cells, CD8+ T cells and Tregs, of which CD4+ T cells can differentiate into T helper 1 (Th1 cells) and T helper 2 (Th2 cells). Th1 cells can enhance the killing ability of T lymphocytes and activate macrophages; Th2 cells can assist B lymphocytes (B cells) to produce specific antigens and exert anti-tumor function; meanwhile, CD4+ T cells can recruit CD8+ T cells and promote tumor growth. Regulatory T cells (Tregs) can reduce NK cells and promote the depletion of effector T cells. TIL-Bs can reduce NK cells and promote the depletion of effector T cells. Secretion of IL-10 or TGF-β by regulatory B cells impairs antitumor immunity and converts quiescent CD4+ T cells into Tregs. NK cells secrete proinflammatory phenotypes that maintain tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs). TANs differentiate into TAN-1 and TAN-2, of which TAN-1 inhibits tumor growth and TAN-2 promotes tumor cell proliferation and metastasis. Mature cells (DC cells) have strong antigen-presenting ability, and can block T cell cycle or apoptosis, and induce Treg cell differentiation. Macrophages are mainly polarized into M1 and M2 macrophages, most of which have antigen-presenting capacity.

Table 2 TCM Formulae in Regulating Tumor Microenvironment

Formulae	Disease Type	Trial Type	Cell Line	Model	Drug Dose	Composition	Mechanism of Action
JYYZXZ^Citation43	GC	Animal vitro	MGC-803	-	Animal: 2 g/kg	Radix Codonopsis pilosulae, Rhizoma Atractylodis macrocephalae, Poria, semen coicis, Radix Angelicae sinensis, Rhizoma Dioscoreae, Radix Aucklandiae, Pericarpium Citri Reticulatae, Smilax Chi, Salviae Chinensis Herba, Radix Glycyrrhizae	TAM regulates the phenotypic transition of macrophages from M2 to M1
YYFZBJS^Citation44	CRC	Animal	HCT 116 MC 38	C57BL/6J ApcMin/^+mice	Animal: L: 3.825 g/kg, M: 7.65 g/kg H: 15.3g/kg	Semen Coicis, Radix Aconiti Lateralis, and Herba Patriniae	YYFZBJS can reduce the number of Treg cells, improve intestinal inflammatory response, and inhibit the occurrence and development of colon cancer.
FLP^Citation45	LC	Animal	Lewis	Nude mice	Animal: 0.2 mL/day (200 mL NS + 84 g FLP)	Astragalus, American ginseng, sand ginseng, wheat winter, white flower snake tongue grass, defeated sauce grass, fist ginseng, peach kernel, notoginseng	FLP can inhibit the expression of IL-2, and then inhibit the differentiation of T cells into Treg cells.
mBYD40^Citation46	GC	-	-	-		Radix astragali; Radix codonopsis pilosulae; Radix angelicae sinensis; Radix glycyrrhizae; Cimicifugae rhizoma; Radix bupleuri; Atractylodes macrocephala, Pericarpium citri reticulatae; Rhizoma Sparganii; Rhizoma	mBYD can promote the proliferation and activation of T lymphocytes, while inhibiting the up-regulation of CD8+PD-1+T cells.
FZJD^Citation47	Acute lung injury	Animal	-	ALI rats	-	Radix Astragali, Codonopsis pilosula, Atractylodes macrocephala, Polygonum multiflorum, Chinese wolfberry, Yunnan Chonglou, Hedyotis diffusa, Actinidia deliciosa	It promoted the transformation of TAM phenotype M2 to M1

Table 3 Herbal Compounds in Regulating Tumor Microenvironment

Compounds	Source	Disease Type	Trial Type	Cell Line	Model	Drug Dose	Mechanism of Action
Astragalus polysaccharides^Citation48–50	Radix Astragali	Proctitis CRC LC	Cell Animal Clinic	H441; H1299; H1437; Lewis; THP;	C57BL/6 mice	Cell: 16 mg/mL Clinic: 500 mg	Increase the CD80 + M1 + M2 / CD206 ratio to accelerate the M1 MDSC polarization; Promote the surface molecules CD80 and CD86.
Lentinan^Citation51	Lentinus edodes	BC LC	Animal	EO771	C57BL/6 mice; FVB mice	1 mg/kg	Promote the proliferation of CD8 + T cells and activation; Induced TAN to N1 phenotype.
Licorice polysaccharide^Citation52	Licorice	CRC	Cell Animal Clinic	CT26	BALB/c mice	Animal: 500 mg/kg	Activate CD4 +T and CD8 + T cells; Increase the number of T lymphocytes; Increase the serum IL - 2, IL-6, IL-7.
Salvia miltiorrhiza polysaccharides^Citation53	Salvia miltiorrhiza	GC	Animal	-	Wistar rats	Animal: 200mg/kg	Improve the anti-inflammatory cytokine (IL-2, IL −4 and IL −10) level, Inhibit proinflammatory cytokines (IL - 6 and TNF alpha).
Asparagus polysaccharides^Citation54	Asparagus	CRC	Cell Animal	MC 38	C57BL/6 mice	Cell: 250 mg/kg 500 mg/kg	Reduce the production of MDSCs or promote the apoptosis of MDSCs; Inhibit the proliferation of MDSCs in MC38 colon cancer mice.
Berberine^Citation55	Coptis chinensis	CACRC	Cells Animal	IMCE; HCT116; RAW 264.7	C57BL/6J-ApcMin/^+ mice	100 mg/kg	Inhibit the production of pro-inflammatory cytokines such as IL-6. and IFN-α in colon macrophages; Reduce the activation of EGFR/ERK signaling pathway in colorectal cancer cells, thus inhibiting the growth of colorectal cancer cells.
Matrine^Citation56	Sophora flavescens	ALL	Clinic	-	-	340 mg/kg	Promote the production of ROS in B-cells; Up-regulated the expression ratio of Bax/Bcl-2 apoptotic genes; Enhanced their immune effects; Improved their anti-tumor effects.
Astragalosid^Citation52,Citation57	Radix Astragali	CRC	Cell Animal	CT 26	Balb/c mice C57BL/6 mice	50 mg/kg	Increase the expression of NKG2D and IFN - gamma of NK cells; Enhance the killing ability of NK cells.
Ginsenosiderg3^Citation58	Ginseng	-	Cell Animal	-	Balb/c mice	-	Reduce the expression of PD-L1 induced by drug resistance and restore t cell toxicity; Promoted the differentiation of M2 macrophages into anti-tumor M1 phenotypes
Resveratrol^Citation59–61	Peanuts, grapes, Polygonum cuspidatum and other plants.	BC	Cell Animal	NK 92; BCap37; MDA-MB-231	C57BL/6 mice	-	Down-regulating PD-1 expression to enhance Th1 immune response; Promote the activation of CD8+T cells; Inhibiting the expression of c-Myc; Inhibiting the secretion of cytokines and the p-STAT2 to reduce the number of T cells and TAM; Inhibite the polarization of M2 macrophages.
Curcumin^Citation62	Turmeric	BC GC CRC	Cell Animal Clinical sample	4T1-Neu MKN-45 CT26	BALB/c mice nude mice	Animal: 50 mg/kg	Reducing in the number of MDSCs and promote its maturity; Promoting CD4+ and CD8+ T cells to produce IFN-γ.
Andrographolide^Citation63	Andrographis paniculata	Colon cancer	Cell Animal	CT 26	C57BL/6 mice	Animal: 5 mg/kg	Increase the CD4 + and CD8 + T cell infiltration and function.
Triptolide^Citation64	Tripterygium wilfordii	melanoma	Cell Animal	B16-F10	C57BL/6 mice	-	Inhibiting TGF - β, VEGF and the production of IL – 10; Reduce the proportion of Treg cells

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