Plant alkaloids play an anti-cancer effect in cancer treatment. By regulating immune function, inhibiting angiogenesis, and inducing cell apoptosis (Efferth and Oesch, 2021). Tetrandrine has a wide range of antitumor effects and can inhibit MDA-MB-231 cell proliferation and induce cellular autophagy by inhibiting phosphatidylinositol-3-kinase (P13K), protein kinase B (AKT), mammalian target of rapamycin (mTOR) pathway (Liu et al., 2016; Guo and Pei, 2019). Reactive oxygen species (ROS) are a class of molecules produced during oxidative stress in the body, which are closely related to tumor immune tolerance and play a key role in immune monitoring (Bailly, 2020; Hu et al., 2021). ROS-triggered small ubiquitin-like modifier (SUMO)-specific protease 3 accumulation is involved in Treg cell-mediated immunosuppression (Yu et al., 2018). In addition to ROS, activation of the Ras, mitogen-activated protein kinase (MAPK) pathway may promote tumor immune evasion in TNBC (Loi et al., 2019). Sinomenine induced apoptosis in MDA-MB-231 cells by upregulating the MAPK pathway and by increasing intracellular ROS production. It also decreased the expression of IL-8, chemokine receptor 2(CXCR2) in MDA-MB-231 cells. Inhibited the activation of nuclear factor kappa-B (NF-κB) and sonic hedgehog signaling pathways in TNBC lung metastasis. (Li et al., 2014; Song et al., 2018; Zhang et al., 2019).

Berberine increased the release of lactate dehydrogenase in MDA-MB-231 cells in a dose-dependent manner, which led to a significant decrease in the secretion of IL-1α, IL-1β, IL-6, and TNF-α at the same time. Synergistic treatment with berberine and lipopolysaccharide significantly reduced the expression of TNF-α and IL- 6 (Zhao et al., 2017; Kim et al., 2018; Lin et al., 2019; Yao et al., 2019; Yao et al., 2019; Zhao and Zhang, 2020). High mobility group box-1(HMGB1) protein is an endogenous member of the proteome called danger-associated molecular pattern that promotes proliferation and survival of a variety of immunosuppressive cells. Synergistic effects of theophylline and berberine induce cell cycle arrest and poly ADP-ribose polymerase (PARP), HMGB1 protein and b-cell lymphoma 2 family-mediated apoptosis in MDA-MB-231 cells (Wild et al., 2012; Hashemi-Niasari et al., 2018).

Cisplatin resistance is associated with breast cancer susceptibility genes. The PARP inhibitor olaparib induces CD8⁺ T cell activation in vivo (Pantelidou et al., 2019; Pettitt et al., 2020). Triptolide downregulates PARP1 levels and inhibits BT549 as well as MDA- MB-231 cell growth, mainly by interfering with X-ray repair cross-complement 1, PAPR1-mediated base excision repair, thereby sensitizing TNBC to cisplatin (Zhang et al., 2019). Both Celastrol and Triptolide inhibit mammosphere formation in MDA-MB-231, BT20 progenitor cells. It inhibited the expression of stem cell marker proteins doublecortin-like kinase 1, aldehyde dehydrogenase, and CD133 (Prominin-1) (Ramamoorthy et al., 2021).

In addition to the above TCM containing alkaloids, such as aconitine, betaine, ephedrine, and evodiamine, which also have antitumor effects (Ma and Wink, 2008; Du et al., 2013; Hyuga et al., 2013; Tan et al., 2020; Zhang et al., 2021), but the immune mechanism of action on TNBC still deserves further investigation.

During tumor progression, tumor cells continuously interact with the microenvironment and mediate immune tolerance. Polyphenols, the active ingredients of TCM, can inhabit the tumor microenvironment (Hui and Chen, 2015; Bian et al., 2020). The ability of breast cancer stem cells to self-renew is closely related to disease progression, and high expression of stem cell estrogen receptor alpha-36 (ER-α36) (Deng et al., 2014). Epigallocatechin-3-gallate is a type of catechin extracted from green tea, effectively inhibited the growth of tumor stem, progenitor cells in MDA-MB-231 and MDA-MB-436 cells and reduced the expression of ER-α36 in these cells (Pan et al., 2016). F-Box and WD repeat domain containing 7 (FBXW7) can inhibit tumor development by acting on the tumor microenvironment (Yumimoto et al., 2015). Honokiol downregulates miR-188-5p via FBXW7, c-Myc signaling, enhances the sensitivity of human breast cancer to doxorubicin. Honokiol exerts anti-proliferative activity during cell cycle arrest in G0/G1 phase and inhibits the proliferation of MDA-MB-231 cells by suppressing the c-Src, epidermal growth factor receptor (EGFR)-mediated signaling pathway. However, due to the limited oral bioavailability of honokiol, the use of vitamin E polyethylene glycol succinate in nanocapillary formulations enhances the anti-cancer effect of in situ TNBC (Park et al., 2009; Godugu et al., 2017; Yi et al., 2021). The NF-κB pathway, a key regulator of the immune response, is frequently dysregulated in cancer (Tegowski and Baldwin, 2018). Magnolol significantly inhibited the activity of highly invasive MDA-MB-231 cells and down-regulated the expression of matrix metallopeptidase 9 (MMP-9), as well as the transcriptional activity of NF-κB and the deoxyribonucleic acid (DNA) binding of NF-κB to the MMP-9 promoter (Liu et al., 2013).

The flavonoids found in TCM have a variety of biological properties, including anti-inflammatory and anti-angiogenic properties, play an immune role by influencing immune organs, cellular immunity, non-specific immunity, and immune-related signal transduction pathways. (Casagrande and Darbon, 2001; Bagli et al., 2004; Ullmannova and Popescu, 2007; Maleki et al., 2019). Puerarin inhibited the migration, invasion and adhesion of lipopolysaccharide-stimulated MDA-MB-231 cells by inhibiting the NF-κB pathway and extracellular regulated protein kinases (ERK) phosphorylation (Liu et al., 2017). However, due to poor water solubility and low bioavailability of puerarin, new puerarin nanoemulsions were developed to induce changes in the immune microenvironment of 4T1 cells, improving the therapeutic efficiency of α-PD-L1 in TNBC models and downregulating intra-tumor ROS (Xu et al., 2020). Licorice flavonoids promote ROS production, increase endogenous and exogenous apoptotic pathways, promote PARP-1 activation in MDA-MB-231 cells, and induce DNA damage. It regulates autophagy and blocks cell growth by inhibiting phosphorylation of AKT and MAPK signaling pathways, regulating the expression of E-cadherin and vimentin (Huang et al., 2019) (-)-Epigallocatechin 3-gallate is a natural polyphenol extracted from green tea, and a series of derivatives were synthesized to improve the pharmacological structure, and all of these compounds were found to exhibit moderate to high cytotoxicity against MDA-MB-231 cells (Crous-Masó et al., 2018).

TCM such as paeonol and curcumin also contain phenolic active ingredients and play an important role in the anti-tumor process (Cai et al., 2014; Hu et al., 2019), which still need to be further explored in the process of immunotherapy for TNBC.

Saponins have pharmacological activities such as antioxidant, anti-inflammatory, and antitumor. The inhibitory effect of ginseng on breast cancer cell growth is mainly through transcriptional upregulation of the cell cycle protein-dependent kinase inhibitors p21 and p53 (Block and Mead, 2003; AL Shabanah et al., 2016). The combination of ginsenoside panaxatriol with paclitaxel inhibited the activation of interleukin-1 receptor-associated kinase 1(IRAK1), NF-κB and ERK1/2, leading to the inhibition of inflammatory factors, and cancer stem cell-related genes expression was downregulated and also inhibited the invasive ability of MB231-PR (paclitaxel-resistant) cells, reducing stem cell properties and resensitizing TNBC paclitaxel-resistant cells to paclitaxel by inhibiting the IRAK1/NF-κB and ERK pathways (Wang et al., 2020). In contrast, ginsenoside Rg1 induces apoptosis through ROS production and inhibits the development of triple negative breast cancer cells (Chu et al., 2020).

Ginsenoside Rh2 induces apoptosis, reverses abnormal differentiation of tumor cells, and resists tumor metastasis, and can be used in combination with chemotherapeutic drugs to increase the effectiveness and reduce the toxicity. Biochanin A combined with ginsenoside Rh2 has a synergistic effect on the proliferation of MDA-MB-231 and MCF-7 cells (Ren et al., 2018). Ginsenoside Rg3 in combination with paclitaxel treatment inhibited NF-kB activation, decreased NF-kB p65 and B-cell lymphoma-2 (Bcl-2) protein expression, and increased Bcl2-associated X and Caspase-3 protein expression, thus promoting the toxicity of paclitaxel on MDA-MB-231, MDA-MB453, and BT-549 cells (Yuan et al., 2017). After analysis using The Cancer Genome Atlas database identified a role for C-X-C motif chemokine ligand 12 (CXCL12), C-X-C motif chemokine receptor 4 (CXCR4) signaling pathway in oncogenic CD8⁺ T cells from human breast cancer, CXCR4 inhibition could enhance the efficacy of immunotherapy in the treatment of metastatic breast cancer (Chen et al., 2019). At doses without significant cytotoxicity, ginsenoside Rg3 treatment resulted in weaker CXCR4 staining in MDA-MB-231 cells, reduced the number of cells migrating during CXCL12-induced chemotaxis, and significantly reduced the number of CD44 ^high/CD24 ^low in MDA-MB-231 cells with therapeutic potential for targeting breast cancer stem cells, possibly through classical mitochondria-dependent caspase activation to induce apoptosis in MDA-MB-231 cells (Chen et al., 2011; Kim et al., 2013; Oh et al., 2019).

Murine double minute2 (MDM2) controls the stability of STAT5 in CD8⁺ T cells and targeting p53-MDM2 interactions is essential for effective antitumor immunity. Polyphyllin D can inhibit MDA-MB-231 cell proliferation by decreasing the expression levels of MDM2, murine double minute x, and mutant p53 and inducing cell cycle arrest by upregulating the expression of MDM2 downstream proteins p21 and p27 (Kong et al., 2016; Zhou et al., 2021). RELT-like protein 2 (Rell2) is a direct target of mircoRNA-18a, and polyphyllin VI increased Rell2 expression and impaired the viability of 4T1 and MDA-MB-231 cells (Wang et al., 2019). Timosaponin AIII, a steroidal saponin, triggers DNA damage in breast cancer, activates the ataxia telangiectasia mutated, cell cycle checkpoint kinase 2 and p38 MAPK pathways, which in turn induces G2/M phase block and MDA-MB-231 apoptosis, and downregulates cell division cycle B1, cell division cycle 2, and cell division cycle 25C. Inhibition of ERK activation through sustained hepatocyte growth factor-induced MDA-MB-231 cell invasion (Tsai et al., 2013; Zhang et al., 2021). Ophiopogonin D significantly inhibits TNBC cell growth and metastasis in vitro, mediated in part by inhibition of the integrin subunit beta 1, focal adhesion kinase, Src, AKT, β-catenin signaling pathway (Zhu et al., 2020).

Polysaccharides isolated from TCM have immunomodulatory and antitumor effects and play an important role in immunosuppression (Chen et al., 2006; Liu et al., 2018). Based on the basis of network-based pharmacology it was determined that astragalus polysaccharide may interfere with the invasion and proliferation of MDA-MB-231 cells by inhibiting PI3KCG/AKT/Bcl2 pathway expression and can promote apoptosis. In vitro experiments it confirmed that astragalus polysaccharide inhibits TNBC symptoms in a dose-dependent manner (Liu et al., 2019b). Huaier polysaccharide inhibited the stem cell-like characteristics of MDA-MB-231, MDA-MB-453 and Hs578T cells in vitro and in vivo, partly through the estrogen receptor α-36 signaling pathway (Hu et al., 2019). Fucoidan inhibits MAPK and P13K activation, suppresses activating protein-1 and NF-κB signaling, downregulates pro-angiogenic factor expression in TNBC cells, exhibits anti-ataxia telangiectasia mutated, cell cycle checkpoint kinase 2 proliferative activity against MDA-MB-231 and HCC1806 cells, and effectively reduces migration and invasion (Hsu et al., 2013; Hsu et al., 2020). Cordyceps polysaccharides effectively inhibited MDA-MB-231 cell metastasis and restored drug sensitivity in topotecan-resistant cells by downregulating the transforming growth factor-β signaling pathway and EMT program (Lin et al., 2016).

Shiitake mushroom polysaccharide, Ganoderma lucidum polysaccharide, polysaccharides from the roots of platycodon grandiflorum, Safflower polysaccharide and Ginseng polysaccharide all have strong anti-tumor activity (Chihara et al., 1969; Ando et al., 2002; Gao et al., 2003; Yoon et al., 2003). However, studies in TNBC are still relatively few and the immune mechanism of action is unclear, which deserves further development.

In addition to the aforementioned drugs, tubeimu also exhibited in vitro inhibition of TNBC cell migration and invasion without significant toxic side effects (Wang et al., 2018). Cantharidin reverses the metastasis of MDA-MB-231 cells by inhibiting pyruvate kinase isozyme type M2 nuclear translocation and disrupting the glucose transporter 1, pyruvate kinase isozyme type M2 glycolytic cycle, leading to the conversion of aerobic glycolysis to oxidation (Pan et al., 2019). More toxic drugs may limit their use in vivo and improve in vivo safety by developing a novel drug, α-amanitin-conjugated trastuzumab, which kills tumor cells while inducing immunogenic cell death, using the HER2 antibody trastuzumab coupled to α-amanitin, and cells containing 17p deletion, which are expressed at low levels of HER2 (Li et al., 2021). Bufalin increased the expression of necrosis mediators threonine kinase1 and threonine kinase3, induced MDA-MB-231 cell death and inhibited the growth of both human breast cancer MCF-7 and MDA-MB-231 cells through the reactive oxygen species-mediated RIP1/RIP3/PARP-1 pathway (Li et al., 2018b).

Arctigenin induces prolonged p21 expression and p38-mediated apoptosis-inducing factor-dependent cell death, which enhanced the toxicity of adriamycin in human breast cancer cells. (Lee et al., 2020). Three triterpenes were isolated from cactus, of which compound d2 was identified as betulinic acid, and treatment of MDA-MB-231 cells with betulinic acid-rich cactus resulted in activation of c-Jun N-terminal kinase as well as downregulation of ERK1 (Foo et al., 2016). Citrus hystrix DC extract and its compounds citronellol and citronellal induce apoptosis in MDA-MB-231 by inhibiting the anti-apoptotic protein Bcl-2, leading to activation of the pro-apoptotic Bcl2-associated X protein and inducing a downstream cystatin-dependent apoptotic pathway by activating cystatin-3 protein (Ho et al., 2020). Rhubarb acid derivatives are new anthraquinones that downregulate Rac1 expression and maybe small molecule inhibitors of Rac1 (Li et al., 2020). Gambogic acid significantly inhibits viability and increases apoptosis of paclitaxel-resistant MDA-MB-231 cells through activation of the sonic hedgehog signaling pathway (Wang et al., 2019). In a word, we have summarized some key ingredients from the above in table 1.