The Crosstalk Between Epithelial-Mesenchymal Transition and Anoikis Resistance: A New Perspective of Traditional Chinese Medicine to Prevent Tumor Metastasis

Introduction

Approximately 90% of cancer-related deaths are attributable to the dissemination of primary tumor cells to distant sites beyond their original location.¹ These malignant cells disseminate via the lymphatic system, bloodstream, or other bodily compartments, eventually colonizing remote tissues where they proliferate. This process, known as metastasis, represents the terminal and most lethal stage of cancer progression.² During metastatic dissemination, the primary tumor invades adjacent tissues and profoundly remodels the surrounding stromal microenvironment. Neoplastic cells subsequently enter the circulation via mechanisms of invasion and intravasation. Upon entry into the bloodstream, tumor cells must adapt to and survive within the fluid, suspension environment.³ These circulating tumor cells then extravasate into distant organs, where they establish micrometastases that may eventually progress to overt metastatic lesions.⁴ A prerequisite for successful metastasis is enhanced cellular motility and invasiveness, which largely depends on dynamic interactions between tumor cells and the stromal components, as well as the induction of epithelial-mesenchymal transition (EMT) in tumor cells.⁵ EMT is characterized by the loss of epithelial features—such as apical-basal polarity and tight intercellular junctions—and the acquisition of mesenchymal traits, including increased motility and invasiveness.⁶ Importantly, the acquisition of EMT characteristics alone does not directly result in metastasis. Tumor cells at the primary site are often anchored to adjacent cells and the extracellular matrix (ECM), and their detachment can trigger a specific form of programmed cell death known as anoikis. Therefore, for tumor cells to survive in the circulation and establish secondary lesions, they must acquire resistance to anoikis.⁷ This resistance is recognized as a hallmark of metastatic potential and is closely linked to tumor cell invasion, intravasation, and distant colonization.⁸ Recent studies have demonstrated that anoikis resistance is a pivotal determinant of the survival of detached cancer cells during metastasis, and its molecular regulation is closely intertwined with EMT. This process is further modulated by multiple microenvironmental adaptation strategies, including redox homeostasis, autophagy, immune evasion, and maintenance of stemness, while the metabolic and epigenetic plasticity associated with EMT can drive cancer cell survival under therapeutic intervention through an EMT–anoikis–metabolism crosstalk, ultimately promoting metastatic dissemination.^9–12 An increasing body of evidence suggests that EMT not only facilitates metastasis but also confers survival advantages by helping tumor cells evade apoptosis induced by external stressors, thereby enhancing cellular viability.¹³ Furthermore, EMT may contribute to the acquisition of anoikis resistance by altering the biochemical composition and mechanical properties of the ECM.¹⁴ These findings point toward a mechanistic interplay between EMT and anoikis resistance in promoting metastasis. However, the precise molecular crosstalk between these processes remains to be fully elucidated.

With advances in molecular biology, increasing evidence has elucidated the molecular targets and mechanisms by which Traditional Chinese Medicine (TCM) inhibits tumor metastasis.¹⁵ An increasing number of studies have consistently shown that the combination of TCM treatment with chemotherapy drugs for tumors can reduce the chances of tumor recurrence and metastasis, prolong the survival period of patients, and improve their quality of life.^16–19 Notably, most active components of TCM are derived from natural plants, which exhibit favorable safety profiles, low toxicity, and good tolerability at clinical doses.²⁰ In contrast to single-target agents, TCM possesses unique advantages in simultaneously regulating multiple signaling pathways and molecular targets, making it highly promising for intervening in complex metastatic networks.^21,22 Additionally, targeted anti-tumor drugs often impose substantial economic burdens on patients, whereas TCM is more economically accessible and holds great potential for widespread development and clinical translation. In this review, we systematically summarise cumulatively the research findings, which investigate the inhibitory effects of TCM on tumor metastasis, particularly through modulation of EMT and anoikis. We aim to elucidate the potential mechanisms underlying the crosstalk between EMT and anoikis in the context of TCM intervention, and discuss these findings in light of the current body of relevant literature (as illustrated in Figure 1).

Figure 1 Visual Summary. Schematic representation of the interaction mechanism of TCM targeting EMT and anoikis resistance to interfere with tumor metastasis.

Crosstalk Mechanism of EMT and Anoikis

The Link Between EMT and Anoikis: ECM Is the Key

The ECM refers to the non-cellular component of tissues that not only provides structural support for resident cells but also constitutes a critical part of their surrounding microenvironment.²³ Although the physical properties and structural composition of the ECM differ across tissue types, its core functions remain highly conserved, including roles in cell adhesion, intercellular communication, and regulation of cell differentiation. Emerging studies have identified that the ECM appears to be a key link between EMT and anoikis, which is mediated primarily through structural and compositional changes in the ECM.²⁴ EMT is characterized by the downregulation of epithelial markers such as cytokeratins and E-cadherin, and the upregulation of mesenchymal markers including N-cadherin, vimentin, and fibronectin.²⁵ This shift in gene expression results in reduced intercellular adhesion and promotes the expression of proteolytic enzymes—particularly matrix metalloproteinases (MMPs), along with fibrinolytic enzymes and histones—that contribute to ECM degradation.²⁶ Moreover, ECM components and signaling molecules altered during EMT, such as fibronectin and vimentin, can engage specific cell surface receptors to activate downstream signaling pathways that promote resistance to anoikis. This, in turn, affects cellular adhesion, migration, and survival.⁷ Importantly, this regulatory relationship is not unidirectional. In tumor cells that have acquired anoikis resistance, the downregulation of epithelial adhesion molecules such as E-cadherin and β-catenin further facilitates the induction of EMT (as illustrated in Figure 2).²⁷

Figure 2 ECM-mediated EMT drives the anoikis-to-anoikis-resistance switch. ECM induces EMT through signal remodeling. The EMT transcription factors, TGF-β, non-coding RNAs and integrin pathways synergistically promote cell invadopodia anoikis resistance, forming a bidirectional regulatory loop to drive tumor invasion and metastasis.

Research has demonstrated that EMT is tightly regulated by a cohort of transcription factors (TFs), including zinc finger E-box binding homeobox 1 (ZEB1), ZEB2, Snail, Slug, and Twist.²⁸ These TFs contribute to anoikis resistance primarily through two mechanisms: the disruption of intercellular junctions and the inhibition of apoptotic signaling pathways. Several of these transcription factors—such as Snail, Slug, ZEB1, and ZEB2 (also known as smad interacting protein 1 (SIP1))—act as direct repressors of E-cadherin by binding to E-box elements within the E-cadherin promoter region.^29,30 In contrast, indirect repression of E-cadherin is mediated by other TFs including Twist1, Twist2, homeobox proteins (e.g., goosecoid (GSC) and SIX homeobox 1 (SIX1)), E2.2, and the forkhead box protein C2 (FOXC2).^31,32 Interestingly, although Twist proteins are typically categorized as indirect repressors, studies have shown that they are also capable of directly binding to E-box2 and E-box3 on the E-cadherin promoter, thereby suppressing its transcription.³³ In addition to repressing epithelial markers, Twist proteins also promote the expression of mesenchymal markers such as fibronectin, vimentin, α-SMA, and N-cadherin.³⁴ Moreover, Twist facilitates the formation of invasive pseudopodia enriched with filamentous actin, which are instrumental in directing the secretion of matrix-degrading enzymes, including MMP7, MMP9, and MMP14. These MMPs degrade components of the extracellular matrix and basement membrane, thereby enhancing tumor cell invasion and metastatic potential.²⁶

The regulatory role of some signaling pathways on ECM was also observed by us. Among them, the cytokine transforming growth factor-β (TGF-β) is widely recognized as a central inducer of both physiological and pathological EMT, particularly within the context of cancer. In malignant cells, the TGF-β/Smad signaling pathway, along with the transcription factor ras responsive element binding protein 1 (RREB1), has been shown to directly upregulate the expression of Snail, a key EMT regulator. This upregulation promotes the activation of fibroblasts and contributes to the development of fibrosis within the tumor microenvironment. The resulting fibrotic milieu facilitates the production of ECM-associated fibrotic mediators that support tumor progression and metastasis.³⁵ Mechanistically, TGF-β ligands form homodimers or heterodimers that bind to their cognate type II and type I transmembrane receptors. Upon ligand binding, the type II receptor phosphorylates the type I receptor, thereby activating its kinase activity. The activated type I receptor subsequently phosphorylates receptor-regulated Smad proteins, which translocate into the nucleus and function as transcription factors to modulate the expression of target genes.³⁶ The TGF-β/Smad signaling axis has been extensively implicated in fibrotic responses across a range of pathological conditions.³⁷ In addition, TGF-β signaling regulates the expression of MMPs, further contributing to ECM remodeling and degradation, thereby facilitating tumor invasion and metastasis.³⁸

Non-coding RNAs are also crucial regulatory parts in the EMT and anoikis processes, and they are usually indirectly regulated through TFs and pathways. As a type of non-coding RNA, microRNA (miRNA) regulates the expression of target genes mainly by binding to the messenger RNA (mRNA) of target genes and affecting their stability and translation activity.³⁹ Several miRNAs have been reported to influence anoikis resistance via modulation of EMT. These include miR-9-5p, miR-10b, miR-139-5p, miR-483-5p, miR-526b-5p, miR-655-3p, and miR-G-10.⁴⁰ Of particular interest is the miR-200 family—comprising miR-200a, miR-200b, and miR-200c—which plays a pivotal role in maintaining epithelial cell characteristics by repressing the expression of EMT-inducing transcription factors ZEB1 and ZEB2.⁴¹ Notably, miR-200c has been shown to modulate EMT in both breast and endometrial cancers and to regulate anoikis resistance via targeting tyrosine kinase receptor B (TrkB).⁴² In addition to miRNAs, lncRNAs also play an important role, and the involvement of these lncRNAs in EMT regulation of anoikis is usually achieved by modulating miRNAs or related signaling pathways.

For instance, long noncoding RNA FOXD2 adjacent opposite strand RNA 1 (lncRNA-FOXD2-AS1) targets miR-7-5p to mediate telomerase reverse transcriptase and promotes anchorage-independent cell growth, whereas lncRNA-H19 facilitates EMT by sequestering miR-29-3p and miR-484, which normally suppress the expression of signal transducer and activator of transcription 3 (STAT3) and Rho-associated coiled-coil containing protein kinase 2 (ROCK2), respectively.⁴³ In thyroid cancer, knockdown of long noncoding RNA small nucleolar RNA host gene 12 (lncRNA-SNHG12) has been shown to inactivate Wnt/β-catenin signaling, thus inhibiting tumor cell migration.⁴⁴ In addition, other lncRNAs involved are long noncoding RNA HOX antisense intergenic RNA (lncRNA-HOTAIR), long noncoding RNA LEF1 antisense RNA 1 (lncRNA-LEF1-AS1), long noncoding RNA maternally expressed gene 3 (lncRNA-MEG3), long noncoding RNA nuclear paraspeckle assembly transcript 1 (lncRNA-NEAT1), and long noncoding RNA TINCR Ubiquitin Domain Containing (lncRNA -TINCR).⁴⁰

The role of the integrin pathway is also of interest. Integrins are a family of transmembrane glycoprotein receptors composed of at least 25 α-subunits and 11 β-subunits, which assemble into more than 20 distinct heterodimeric integrin complexes through non-covalent interactions.⁴⁵ Integrins mediate EMT progression in tumor cells via multiple signaling cascades, including FAK, PI3K/AKT, and mitogen-activated protein kinase (MAPK) pathways, and EMT itself can further promote the upregulation of specific integrin subtypes.⁴⁶ This bidirectional regulation contributes to enhanced tumor cell plasticity and metastatic potential. In normal epithelial tissues, cells predominantly express the collagen receptor α2β1 and the laminin receptors α3β1 and α6β1. In contrast, hyperproliferative epithelial cells and various carcinomas frequently exhibit overexpression of integrins such as αvβ5 and αvβ6. Notably, αvβ6 is strongly upregulated in dermatofibrosarcoma and other aggressive tumors. These changes in integrin expression patterns are closely related to the enhanced ability of cell invasion and the increased resistance of cells to detachment from the adherent state, thereby facilitating the survival of tumors during the metastasis process.⁴⁷

EMT and Anoikis: Involvement of Apoptotic Signaling

Mechanisms of anoikis include regulation of the expression of Bcl-2 and Bax family-related genes, and activation of the caspase family (as illustrated in Figure 3).⁴⁸ Bcl-2 serves as a principal anti-apoptotic protein, functioning to preserve mitochondrial membrane integrity and thereby prevent apoptosis.⁴⁹ In contrast, Bax, a pro-apoptotic member of the same family, promotes mitochondrial membrane permeabilization and is primarily localized to the mitochondrial outer membrane.⁵⁰ In the case of esophageal squamous cell carcinoma (ESCC), Twist1 has been shown to inhibit apoptosis by upregulating Bcl-2 and downregulating Bax, thereby contributing to anoikis resistance.⁵¹ Another critical pro-apoptotic regulator is Bim, which initiates intrinsic apoptotic signaling and is often considered a key inducer of anoikis. EMT-associated TFs regulate these apoptosis-related proteins at the transcriptional level. For example, ZEB1 suppresses Bim expression by directly binding to its promoter region, thereby promoting anoikis resistance.⁵² Similarly, silencing of Slug and Snail has been found to restore Bim expression and sensitize tumor cells to anoikis. Beyond gene regulation, these TFs also interfere with apoptotic signaling pathways, including the mitochondrial (intrinsic) pathway, and key apoptotic effectors such as caspases.⁵³ A complex network of interconnected signaling pathways underlies the crosstalk between EMT and anoikis. Key pathways implicated include TGF-β, Wnt/β-catenin, PI3K/AKT, Notch, and Hedgehog. These pathways not only modulate EMT and ECM remodeling but also influence apoptosis by regulating EMT-TFs and apoptotic regulators. In breast cancer, for instance, TGF-β receptor 3 mediates anoikis through activating transcription factor 4 (ATF4).⁵⁴ The Wnt/β-catenin pathway contributes to anoikis resistance by inducing MMP expression and regulating TFs such as Snail, Slug, and Twist.⁵⁵ GLI is an effector protein of the Hedgehog signaling pathway, which plays a crucial part in cell adhesion and apoptosis.⁵⁶ It has been found that GLI2 increases anoikis resistance, whereas silencing of GLI, on the other hand, induces anoikis.⁵⁷ This may be attributed to Hedgehog-mediated upregulation of Snail and Slug.⁵⁸ Furthermore, in colorectal cancer (CRC), GLI2 has been reported to promote immune escape and anoikis resistance through TGF-β-mediated Hedgehog signaling.²⁷ Of particular interest are the PI3K/AKT and Notch signaling pathways, both of which can directly downregulate E-cadherin expression, distinguishing them from many other signal transduction mechanisms.⁵⁹ Activation of PI3K/AKT enhances Bcl-2 expression and inhibits anoikis, while Notch pathway activation promotes cell survival and proliferation under anchorage-independent conditions, thereby reinforcing anoikis resistance.^59,60

Figure 3 EMT Orchestrates Anoikis Resistance through Integrated Apoptotic Signaling and Metabolic Reprogramming. The schematic diagram illustrates the dual mechanism by which EMT mediates resistance to disintegrated apoptosis: by regulating apoptosis-related molecules such as Bcl-2 and Bax, the caspase family, as well as pathways such as TGF-β and PI3K/AKT to inhibit apoptosis, and simultaneously regulating metabolic reprogramming such as ROS levels and glycolysis, as well as molecules such as PDK4 and CEMIP, to help tumor cells adapt to the metabolic pressure after detachment from the ECM.

EMT Regulates Anoikis: Interference with Metabolic Reprogramming

Several studies have identified the significance of metabolic reprogramming reconfiguration in the interplay between EMT and anoikis (as illustrated in Figure 3). Among the key metabolic regulators, reactive oxygen species (ROS) have been shown to play a dual and complex role in anoikis resistance, although the precise molecular mechanisms remain incompletely understood.⁶¹ On one hand, physiological levels of ROS are essential for maintaining cell proliferation and adhesion. On the other hand, elevated ROS levels in cancer cells can promote anoikis resistance through the activation of chronic pro-survival signaling pathways.⁶² In prostate cancer, the EMT transcription factor Snail has been implicated in the regulation of ROS production, and its overexpression is associated with increased ROS levels that contribute to anoikis resistance.⁶³ Under normal physiological conditions, detachment of epithelial cells from the ECM leads to impaired glucose transport, reduced adenosine triphosphate (ATP) production, and ultimately the induction of apoptosis. In contrast, metastatic cancer cells circumvent this energy stress through oncogene-driven metabolic adaptations, including enhanced glycolysis and fatty acid oxidation, which collectively support survival under anchorage-independent conditions.⁶¹

In human mammary epithelial cells, pyruvate dehydrogenase kinase 4 (PDK4)—upregulated via activation of estrogen receptor γ—induces a metabolic shift that reduces the conversion of pyruvate into acetyl-CoA, thereby suppressing glucose oxidation and enhancing anoikis resistance.⁶⁴ Another critical regulator is cell migration-inducing protein (CEMIP), which plays multiple roles in cell migration, invasion, and metabolic regulation. CEMIP promotes the production of pyruvate and lactate, supports intracellular ATP homeostasis, and enhances resistance to anoikis upon detachment from the ECM.⁶⁵ Mechanistically, CEMIP facilitates the translocation of protein kinase C alpha (PKCα) by inducing calcium release from the endoplasmic reticulum, which in turn promotes anoikis resistance and augments metastatic potential. At the plasma membrane, PKCα activates protective autophagy by disrupting the Bcl-2/Beclin-1 complex, enabling detached cells to survive under metabolic stress.⁶⁶

The Mechanism by Which Dead Cells Promote Tumor Metastasis

In addition to the acquisition of anoikis resistance by tumor cells via EMT to survive upon matrix detachment, recent studies have revealed a critical reverse perspective: cells that die upon detachment from the primary site can themselves act as drivers that promote the invasion and migration of residual tumor cells. This bidirectional interaction renders the relationship between cell death and tumor progression far more complex (as illustrated in Figure 4). Anoikis is classically executed primarily through the apoptotic pathway, characterized by caspase-3 activation and loss of mitochondrial membrane potential.⁶⁷ However, recent studies have demonstrated that cells deprived of matrix adhesion can also undergo death via alternative pathways, including ferroptosis,⁶⁸ and autophagy-dependent cell death,⁶⁹ indicating that anoikis itself exhibits diversity in cell death modalities.

Figure 4 Diverse Cell Death Modalities and Their Bidirectional Crosstalk with Tumor Metastasis via Anoikis Regulation. The schematic diagram illustrates the diverse death modes of detached apoptosis (apoptosis, ferroptosis, autophagy-dependent cell death) and their bidirectional interaction with tumor metastasis, including the release of signals by dead cells promoting the invasion and migration of residual tumor cells, as well as the crosstalk among different death modes forming a positive feedback loop of “death-survival-metastasis”.

Studies have revealed that apoptotic tumor cells release S100a4-containing nuclear expulsion products into the extracellular space via a Padi4-mediated nuclear expulsion process. These products activate the advanced glycosylation End-Product specific receptor (RAGE) receptor on the surface of neighboring surviving cells, triggering the Erk signaling pathway and markedly enhancing the metastatic capacity of residual cancer cells.⁷⁰ Ferroptosis is an iron-dependent form of cell death driven by lipid peroxidation.⁷¹ Recent research has established its double-edged role: on one hand, ferroptotic stress enhances tumor cell antigenicity and the release of danger signals, activating anti-tumor immune responses; on the other hand, lipid peroxides and damage-associated molecular patterns (DAMPs) released by ferroptotic cells can induce the polarization of tumor-associated macrophages toward an M2 phenotype and promote the formation of neutrophil extracellular traps (NETs). NETs have been shown to capture circulating tumor cells and facilitate their colonization.^72,73 A study in ovarian cancer reported that upon matrix detachment and spheroid formation, cells acquire ferroptosis resistance by efficiently utilizing iron ions to compensate for the loss of extracellular matrix.⁷⁴ During this process, iron metabolic reprogramming not only supports resistance to anoikis but also strengthens cell invasiveness. Autophagy, as a programmed cell death mechanism, plays an especially complex role in tumor metastasis. Studies in breast cancer have demonstrated that BR serine/threonine kinase 2 (BRSK2) associates with the Vps34-class III PI3K–Beclin-1–Autophagy Related 14 (ATG14) autophagy signaling complex, protecting cancer cells from anoikis and nutrient deprivation. Inhibition of BRSK2 significantly reduces autophagic activity, enhances apoptosis, and suppresses metastasis.⁷⁵ Furthermore, autophagy promotes the EMT program by degrading epithelial markers such as E-cadherin. For instance, IGF2BP3, an m⁶A-binding protein, promotes cap-independent translation of c-Met by binding to m⁶A-modified sites on c-Met mRNA. This in turn regulates autophagy-mediated EMT via the c-Met/PI3K/AKT/mTOR pathway, driving metastasis in triple-negative breast cancer.⁷⁶ This finding uncovers an intricate regulatory network linking epigenetic modification, autophagy, and EMT. Notably, apoptosis, ferroptosis, and autophagy do not act independently but engage in an elaborate crosstalk network.⁷⁷ This crosstalk allows one form of cell death within the tumor microenvironment to amplify the pro-metastatic effects of other death modalities via signal integration, forming a positive feedback loop of “death–survival–metastasis”.⁷⁸ Although multiple mechanisms by which dying cells promote metastasis have been uncovered, whether these findings are pan-cancer relevant and can be translated into universal therapeutic targets remains to be validated in larger tumor cohorts, across more cancer types, and in models that more closely recapitulate clinical settings.

Mechanisms of Inhibition of Tumour Metastasis by TCM

Research on single herb extracts and TCM formulations has shown that TCM can inhibit tumors by intervening in ECM, regulating apoptosis genes, controlling metabolism, and non-coding RNA. Table 1 summarizes detailed information on the active ingredients of single herbs, including their scientific names, traditional uses, effective dosages, routes of administration, and reported applications in oncology. Table 2 presents the composition and traditional therapeutic functions of classical TCM prescriptions, along with their documented roles in cancer treatment. Table 3 provides a comprehensive overview of how TCM influences tumor metastasis by targeting the mechanisms mentioned above, including EMT, anoikis resistance, and their upstream regulatory pathways.

Table 1 TCM Understanding of Herbs and Compounds

Table 2 TCM Understanding of Formulae

Table 3 Potential Mechanism of TCM Targeting EMT Mediating Anoikis

Intervening in the ECM

TCM has been shown to inhibit tumor metastasis through multiple mechanisms, including indirect regulation of the ECM via signaling pathways and TFs, as well as direct remodeling of ECM structure and composition, thereby modulating EMT and enhancing resistance to anoikis. For example, honokiol, a major bioactive compound from Magnolia officinalis, CT1-3, a novel hybrid derived from Magnolia officinalis and Brassica oleracea L., and Rosthorin A, extracted from Isodon rosthornii, have all been reported to downregulate Snail/Slug and promote E-cadherin expression, thereby inhibiting EMT.^79–81 Both Inulae Flos and Magnolia officinalis are qi-regulating drugs. Unlike Honokiol, which targets Snail, Inula japonica Thunb specifically binds to ZEB1 in triple Negative Breast Cancer (TNBC) and induces its ubiquitination to suppress cell invasion and metastasis.⁸² In ovarian cancer, Isoliquiritigenin (extracted from Glycyrrhiza uralensis Fisch) similarly inhibits metastasis by targeting ZEB1. Additionally, triptonide (from Tripterygium wilfordii) has been shown to induce the lysosome-mediated degradation of Twist1, subsequently reducing Notch1 expression and NF-κB phosphorylation.⁸³

Most TCM agents exert their regulatory effects on EMT and anoikis through upstream signaling pathways rather than direct interaction with TFs. The Wnt/β-catenin, TGF-β/Smad, and PI3K/AKT pathways are most frequently implicated. Various compounds—such as Astragalus polysaccharides (Astragalus membranaceus), extracts from Garcinia hanburyi, gallic acid (Rhus chinensis), Euphorbia factor L2 (Euphorbia pekinensis), and Radix Sanguisorbae—have been shown to inhibit EMT via modulation of the Wnt/β-catenin pathway.^84–89 Radix Sanguisorbae has shown significant efficacy in 5-fluorouracil-sensitive and resistant CRC.⁸⁸ Several TCM formulas targeting the TGF-β/Smad pathway have also been identified, including BFD, BBD, FZXJJZF, and RYF.^90–93 In addition, compounds such as pomelo, Hemsleya amabilis, and acacetin (from Radix Pseudostellariae) inhibit tumor invasion and metastasis via regulation of the PI3K/AKT signaling pathway.^94–96 Notably, glycogen synthase kinase-3 (GSK-3) acts as a downstream effector of this pathway, mediating the expression of EMT-related TFs. The formulas BJJP and JSD have been shown to suppress liver and colon cancer metastasis via the AKT/GSK-3β/Snail axis,^97,98 while Homoharringtonine (extracted from Cephalotaxus hainanensis) targets the PI3K/AKT/GSK-3β/Slug pathway to inhibit liver cancer progression.⁹⁹ The JAK/STAT signaling pathway also plays a central role. STATs are activated through JAK-mediated phosphorylation and translocate to the nucleus to regulate target gene transcription.¹⁰⁰ TCM compounds such as 18-β-glycyrrhetinic acid (Glycyrrhiza uralensis), a flavonoid glycoside from Murraya paniculata, and fraxetin (from Fraxini Cortex) have all been reported to inhibit STAT3 activity,^101,102 while Ganoderma Lucidum Polysaccharide (extracted from Ganoderma lucidum) suppresses EMT in cervical cancer via the JAK/STAT5 pathway.¹⁰³

Recent studies have also highlighted the role of TCM in regulating non-coding RNA networks. For example, puerarin (from Pueraria lobata) inhibits EMT and suppresses hepatocellular carcinoma (HCC) metastasis by modulating the miR-21/PTEN/AKT pathway.¹⁰⁴ In breast cancer (BC), the TCM formula RYP has been shown to suppress tumor metastasis via the miR-134/Slug axis.¹⁰⁵ Sodium new houttuyfonate (extracted from Houttuynia cordata Thunb) targets the linc00668/miR-147a/Slug axis, while BXXXD targets lncRNA TUC338 to mediate EMT.^106,107

In addition, some TCMs directly alter ECM components, such as upregulating the epithelial marker E-cadherin and downregulating the mesenchymal marker N-cadherin, thereby mediating EMT. Dihydroartemisinin, a derivative of Artemisia carvifolia, has been found to effectively inhibit gastric carcinoma (GC) proliferation. Furthermore, increasing drug concentrations significantly enhances E-cadherin expression while inhibiting the protein expression of the mesenchymal marker Vimentin.¹⁰⁸ Scorpion (Buthus martensii Karsch), the dried whole scorpion of the Buthidae family, is commonly used in TCM to treat internal and external wind-related conditions, such as infantile convulsions, facial paralysis due to stroke, hemiplegia, tetanus, and rheumatism. Its compatibility with Astragalus in treating tumors has also been validated by modern molecular biomedical research.¹⁰⁹ Studies have found that Scorpion promotes E-cadherin and inhibits N-cadherin to mediate EMT.¹¹⁰ Alkaloids extracted from Catharanthus roseus have long been used in oncology; notably, vinorelbine modulates the expression of E-cadherin, N-cadherin, vimentin, Snail, and matrix metalloproteinases MMP-2 and MMP-9, thereby suppressing cancer cell invasion and metastasis.¹¹¹ Vinorelbine (extracted from Catharanthus roseus) regulates E-cadherin, N-cadherin, Vimentin, and Snail, MMP-2, and MMP-9 to inhibit cancer cell metastasis. Integrins and MMPs play important roles in maintaining ECM structural stability.¹¹² It has been reported that Cardamonin (extracted from Alpinia katsumadai) effectively reduces MMP-2 and MMP-9 expression in tumor cells, thereby increasing ECM adhesion effects.¹¹³ Similarly, TCM formulas such as XLLXF and FZKAD have similar effects.¹¹⁴ Other agents, including JFK and osthole (from Cnidium monnieri), regulate ECM dynamics through the integrin/Src pathway and ITGα3/ITGβ5 signaling, respectively.¹¹⁵

Regulation of Apoptotic Genes

Some TCMs exert anti-tumor effects primarily by regulating apoptosis-related genes downstream of EMT-associated signaling pathways. For instance, berberine (extracted from Coptidis Rhizoma) has been shown to inhibit EMT through the TGF-β pathway, while also promoting the apoptosis of colon epithelial cells induced by tumor-associated fibroblasts.¹¹⁶ Similarly, Chlorogenic acid (extracted from Lonicerae) induces apoptosis of BC cells through the NF-κB signaling pathway.¹¹⁷ In addition to inhibiting the expression of EMT proteins, Cinnamaldehyde (extracted from Cinnamomum cassia) has been found to induce apoptosis of non-small cell lung cancer (NSCLC) through the Wnt/β-catenin pathway.⁸⁵ Furthermore, several TCM-derived compounds induce apoptosis through cell cycle arrest. For example, ursolic acid (from Eriobotryae Folium) arrests the cell cycle at the G0/G1 phase, thereby triggering caspase-dependent apoptosis.⁶⁰ Similarly, Paris polyphylla ethanol extract induces G2/M arrest in bladder cancer cells and inhibits invasion, migration, and EMT of melanoma cells by activating autophagy.^118,119 Likewise, the root extract of Hemsleya amabilis Diels promotes apoptosis via G2/M arrest, modulates the expression of Bax and Bcl-2, and inhibits renal cell carcinoma cell proliferation through suppression of the PI3K/AKT signaling pathway.⁹⁶

Participate in Metabolic Reprogramming

A study in NSCLC reported that in NSCLC A549 cells, the reconstructed mixture of baicalein, wogonin, and oroxylin-A was shown to inhibit EMT via modulation of the PI3K/Akt–TWIST1 axis, with proteomic evidence implicating suppression of the glycolytic pathway, suggesting a potential metabolic effect despite lacking direct mechanistic proof of metabolic reprogramming.¹²⁰ More compellingly, Oroxylin-A has been demonstrated to inhibit glycolysis-dependent proliferation in breast cancer by activating sirtuin 3 (SIRT3), destabilizing hypoxia inducible factor 1 subunit alpha (HIF-1α), and increasing superoxide dismutase 2 (SOD2) expression and activity, thereby providing concrete evidence of metabolic reprogramming by a TCM-derived compound.¹²¹ Although direct evidence for the role of TCM in regulating ROS during EMT is currently lacking, some studies suggest that certain Chinese herbal extracts may affect tumor progression through ROS-mediated autophagy. For instance, the ethyl acetate extract of Biancaea sappan and a novel aniline derivative isolated from Peganum harmala L. have been shown to modulate tumor development by activating autophagy via ROS signaling.¹²²

Discussion and Conclusion

Currently, the application of TCM in clinical oncology is both widespread and gaining increasing recognition, particularly in the prevention and management of tumor recurrence and metastasis. Research to date has demonstrated that TCM-derived compounds or individual constituents possess the capacity to impede the process of EMT and re-sensitize tumor cells to anoikis-induced apoptosis. These effects are mediated through the modulation of multiple biological processes, including tumor metabolism, ECM remodeling, transcription factor activity, signaling pathway regulation, and non-coding RNA expression. Therefore, targeting EMT and anoikis via TCM-based interventions represents a promising and novel research direction for limiting tumor invasion and metastasis.

However, current studies in this field face several limitations. Many investigations lack robust in vivo validation, such as the use of appropriate animal models, and fail to incorporate assessments of functional recovery or molecular interactions to substantiate mechanistic findings. Moreover, because most of the existing evidence is derived from in vitro experiments, animal studies, or investigations with relatively small sample sizes, substantial heterogeneity exists in study methodologies, dosing strategies, model selection, and outcome measurements. Such variability reduces the comparability across studies and may impose limitations on the interpretation of the results. In addition, some of the reported findings have yet to be validated in large-scale, rigorously designed clinical trials; therefore, the current conclusions should be interpreted with appropriate caution. To address these gaps, future research should adopt more rigorous and systematic approaches to elucidate the precise mechanisms underlying TCM’s regulatory effects on EMT and anoikis. Moreover, identifying additional molecular targets and signaling pathways will further advance our understanding of how TCM can enhance tumor cell susceptibility to anoikis. These efforts will ultimately enrich the modern scientific foundation of TCM and support its role in suppressing tumor metastasis through evidence-based strategies.