Mechanistic and Clinical Perspectives on Traditional Chinese Medicine in Thyroid Cancer Management.

INTRODUCTION

Cancer poses a major threat to global public health, with incidence and mortality rates continuing to rise ( Wang et al. , 2026 ). According to the 2022 GLOBOCAN estimates from the International Agency for Research on Cancer, thyroid cancer accounted for approximately 821,000 new cases and 47,500 deaths worldwide, ranking seventh among all cancers globally and fifth among women, with a markedly higher incidence in females than in males ( Lyu et al. , 2024 ). Thyroid cancer has transitioned from being a rare malignancy to the most common cancer of the endocrine system. The disease demonstrates a marked sex disparity, with a female-to-male ratio of approximately 3:1 ( Kitahara and Schneider, 2022 ). Despite its high incidence, thyroid cancer generally has a favorable prognosis, with approximately 44,000 deaths reported annually. Moreover, thyroid cancer affects individuals across all ages, with a median age at diagnosis of 51 years ( Chen et al. , 2023c ). The highest incidence occurs between the ages of 45 and 64 years. Of particular concern is that it is the most frequently diagnosed cancer of adolescents and young adults under the age of 40 years, with higher rates reported in parts of East Asia, North America, and certain European countries ( Li et al. , 2024a ).

Thyroid cancer progression and therapeutic resistance are strongly associated with genetic alterations, including mutations in the B-Raf proto-oncogene (BRAF), RAS, RET, and Promoter of Telomerase Reverse Transcriptase (TERT), which are frequently shared among different tumor subclones ( Deng et al. , 2026 ). This branched clonal evolution contributes to tumor progression, intratumoral heterogeneity, and dedifferentiation ( Puliafito et al. , 2022 ). Epigenetic alterations and divergent transcriptional programs further contribute to functional heterogeneity. This includes variable activation of oncogenic pathways and differential expression of thyroid differentiation markers such as the sodium–iodide symporter, thereby influencing radioactive iodine responsiveness ( Zhang et al. , 2025a ). Single-cell studies show that different cellular states, including proliferative, inflammatory, and stem-like phenotypes, coexist within thyroid tumors, reflecting their high phenotypic plasticity ( Grassi et al. , 2021 ).

Based upon the heterogeneity, resistance and recurrence arise due to the coordinated molecular and cellular changes. Mitogen-Activated Protein Kinase (MAPK) pathway reactivation, especially in tumors carrying the BRAF V600E mutation or mutant RAS proteins, maintains ERK signaling and drives proliferation and dedifferentiation despite targeted therapy ( Li et al. , 2025a ). Simultaneous PI3K/AKT/mTOR activation by PTEN loss or PIK3CA mutations enhances tumor survival and aggressiveness, particularly in poorly differentiated and anaplastic subtypes ( Forma et al. , 2025 ). TERT promoter mutations, especially those carrying the BRAF V600E mutation, drive telomerase activation and genomic instability, increasing the risk of recurrence ( Elliott et al. , 2024 ). Radioiodine resistance is mainly caused by dedifferentiation, leading to decreased sodium-iodide symporter activity and suppression of thyroid-specific genes due to hyperactivation of the MAPK ( Landa and Cabanillas, 2024 ).

Moreover, the tumor microenvironment (TME), with regional variation in immune infiltration, hypoxia, vascular remodeling, and stromal structure, is another factor relevant to therapy resistance in thyroid cancer ( Cunha and Ward, 2022 ). This local and molecular heterogeneity facilitates clonal evolution in response to treatment pressure, thereby favoring the growth of resistant subpopulations and increasing the likelihood of recurrence ( Febrero et al. , 2024 ). Such dynamic tumor adaptation reflects the combined effects of dedifferentiation, epigenetic reprogramming, microenvironmental remodeling, and the persistence of minimal residual disease ( Xu et al. , 2023 ). Collectively, these processes make risk stratification more problematic and restrain long-term therapeutic outcomes ( Li et al. , 2024b ). Hence, to overcoming resistance in thyroid cancer requires integrative molecular profiling and rationally developed combination strategies that simultaneously target tumor-intrinsic drivers and microenvironmental dependencies.

First-line management of thyroid cancer includes surgery, radioiodine ablation in differentiated subtypes, and TSH suppression, achieving high cure rates in early papillary and follicular tumors ( Frisco et al. , 2023 ). Total thyroidectomy with appropriate lymph node dissection is recommended in many cases, including medullary and selected resectable anaplastic cancers ( Pavlidis et al. , 2023 ). However, 33 to 50% of differentiated thyroid cancers eventually become radioiodine-refractory or present as unresectable or metastatic disease, necessitating systemic therapy ( Yamauchi and Yabe, 2025 ). In this setting, second-line treatments such as tyrosine kinase inhibitors and mutation-specific targeted agents can improve progression-free survival but rarely induce complete remission and are associated with higher toxicity ( Coca-Pelaz et al. , 2023 ). Conventional chemotherapy remains largely palliative in advanced refractory disease ( Pereira et al. , 2020 ). Consequently, the limited long-term efficacy and toxicity associated with current therapeutic approaches highlight the need for safer and more effective alternative or complementary treatment strategies ( Gigliotti and Jasim, 2024 ).

Natural products provide a vast resource for the development of anti-tumor drugs, which have been investigated for decades ( Huang et al. , 2021 ). The morbidity and mortality rates of the malignant tumor are high, and hence, the latest therapeutics combine different features into one, with molecular targeted chemotherapy being frequently employed ( Naeem et al. , 2022 ). The attraction of easy access and with fewer side effects and toxicity attracted much attention to the use of traditional Chinese medicine (TCM) as chemotherapy or adjuvant chemotherapy ( An et al. , 2025 ). The use of TCM in the prevention and treatment of various diseases in China and other Asian countries dates back more than a thousand years. In medicine, botanical products derived or extracted for therapy are based on natural products and medicinal plants rich in bioactive compounds, serving as sources of therapeutic agents ( Liu et al. , 2024 ). At the beginning of the last century, 80% of drugs were derived from natural materials, and approximately a quarter of drugs prescribed today are derived from plants worldwide ( Ke et al. , 2022 ). In recent times, TCM have received considerable attention and have already become a new area of cancer studies. Nature is abundant in anticancer TCM-derived compound, and most of them have shown considerable antitumor effects without severe toxicity or side effects compared with conventional chemotherapeutic agents ( Chen et al. , 2023a ).

This review aims to evaluate the mechanistic basis and clinical potential of TCM in the management of thyroid cancer. It highlights the molecular pathways involved in tumor progression and resistance, examines how TCM compounds may modulate these signaling networks to inhibit growth and enhance therapeutic response, and summarizes current preclinical and clinical evidence, identifying research gaps and future directions for integrative treatment strategies.

PATHOPHYSIOLOGY OF THYROID CANCER

Clinicopathological characteristics of thyroid cancer

Thyroid cancer occurs due to follicular or para-follicular epithelial cells, which is the most prevalent head and neck cancer. Histologically, thyroid cancer may be categorized into several types, including papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), medullary thyroid carcinoma (MTC), and anaplastic thyroid carcinoma (ATC), with PTC being the most common ( Luvhengo et al. , 2023 ). Subsequently, PTC, which comprises 85-90% of thyroid malignancies, is characterized by papillary structures and is a positive prognostic factor, but recurrence and lymph node spread remain clinical problems ( Al-Abbadi et al. , 2025 ). Thus, FTC, which accounts for 10 percent of cases, is more invasive and characterized by a higher rate of distant dissemination, such as the lungs and bones, than PTC, which requires more specific and tailored treatment ( Dong et al. , 2022 ).

Furthermore, MTC pathogenesis is largely linked to defects in the rearranged during transfection (RET) proto-oncogene and has a significant hereditary predisposition, especially through gain-of-function mutations, which require extensive genetic counseling and multidisciplinary strategies to achieve optimal clinical outcomes ( Pavlidis et al. , 2021 ). Although ATC accounts for only 1-2% of all thyroid malignancies, it is the most aggressive ( Bolin, 2021 ). It is characterized by a lack of differentiation, rapid progression, a poor prognosis, and low sensitivity to current treatments ( Bolin, 2021 ).

Cellular alterations

The main cellular characteristics of thyroid cancer include the presence of cancer stem-like cells (CSCs), which can self-renew and differentiate and are associated with greater tumorigenicity, metastatic capacity, and resistance to chemoradiation ( Rao and Smallridge, 2023 ). These CSCs are found across major thyroid cancer subtypes and can be detected by markers such as CD133, CD44, and aldehyde dehydrogenase ( Elia et al. , 2022 ). Additionally, epithelial-mesenchymal transition (EMT) contributes to tumor aggressiveness, and the detection of EMT markers has helped elucidate mechanisms of invasion and metastasis ( Bogusławska et al. , 2022 ).

Genetic drivers and molecular subtypes

Thyroid cancer is a disease that is characterized by inherited and somatic genetic changes. In MTC, familial cases are typified by mutations in the RET proto-oncogene. In contrast, in familial non-medullary thyroid cancer, the familial thyroid cancer is typified by autosomal dominant mutations with variable penetrance ( Carneiro et al. , 2024 ). Hereditary and sporadic cases have several susceptibility genes being identified, including HABP2, DUOX2, and WDR77 ( Han et al. , 2019 ). BRAF, RAS, RET/PTC rearrangements (in PTC), PAX8/PPARG rearrangements (in FTC) are all subtype-specific mutations, which are useful in the classification of histological subtypes as well as in the selection of treatment options. There are also polymorphisms in DNA repair genes that may increase cancer risk, such as XRCC3 rs861539 and XPC 2228001 ( Sipos and Ringel, 2023 ).

Alterations in the PI3K pathway: Increased PI3K signaling is a characteristic of thyroid cancer, especially the FTC subtype. This pathway has mutations in the GTPase RAS and the alpha subunit of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA), serine-threonine protein kinase (named AKT), and phosphatase and tensin homolog (PTEN) ( Landa and Cabanillas, 2024 ). Although it is assumed that RAS mutations represent an early event in thyroid cancer tumorigenesis, other downstream pathway effectors are dysregulated in less differentiated histotypes of thyroid cancer ( Fig. 1 ) ( Avagliano et al. , 2022 ).

AKT: The AKT mutation, such as the E17K single-point mutation, results in constitutive plasma membrane localization and prevents apoptosis in thyroid cells. Subsequently, copy numbers of AKTs and other proteins increase. Mutations in AKT, particularly in the context of PIK3CA, occur later during thyroid tumor development and are more common in poorly differentiated thyroid carcinomas (PDTCs) (19%) ( Alzahrani, 2023 ).

PIK3CA: PIK3CA may harbor either an activating mutation or a copy number increase. There are missense mutations in exons 9 and 20 (E542K, E545K, and H1047R), but they are less frequent than the amplifications at chromosome 3q26.3 ( Yu and Liu, 2026 ). These events promote PIK3CA protein upregulation, but their tumorigenicity is poorly described. PIK3CA mutations and copy number gains are mutually exclusive in well-differentiated thyroid carcinomas (WDTCs) but may coexist in less differentiated tumors, where they contribute to disease progression. In ATCs, PIK3CA mutations are common, whereas in FTCs and PDTCs, they are rare ( Pinto et al. , 2022 ).

PTEN: Mutations in the tumor suppressor PTEN lead to constitutive activation of the PI3K pathway, driving increased cell proliferation, motility, and protein synthesis. The mechanisms that cause PTEN inactivation include mutations, loss of heterozygosity, deletions, and epigenetic alterations that lead to PTEN downregulation. FTCs are characterized by alterations, which are common and increase with the progression of the thyroid tumor (4% in PDTCs and 15% in ATCs) ( Table 1 ) ( Hong et al. , 2022 ).

RAS: Unlike thyroid cancer mutations in the PI3K pathway, RAS mutations have similar effects across all variants. They are shared actions in both the PI3K and MAPK pathways ( Fig. 1 ). Three RAS gene codons (G12, G13, and Q61) can be mutated, although most thyroid tumor mutations occur at Q61 ( Alzumaili and Sadow, 2023 ). Such mutations activate RAS (locking it in the GTP state) and stabilize it in cells. 30-50% of FTCs harbor RAS point mutations, whereas in sporadic MTCs, which share a RET mutation, RAS and RET mutations are mutually exclusive, and 10-45% of these harbor RAS point mutations. Additionally, RAS mutations are found in PTCs (5%) and in PDTCs and ATCs (approximately 25% each) ( Table 1 ) ( Lee et al. , 2023 ).

Epigenetic deregulation: In addition to the SWI/SNF members, next-generation sequencing (NGS) of PDTC/ATC showed that other sets of epigenetic regulator mutations are selected in progressive thyroid tumors. These are histone methyltransferases (KMT2A, KMT2C, KMT2D, and SETD2 genes) and histone acetyltransferases CREBBP and EP300 ( Liu et al. , 2023 ). The defective thyroid in which such mutations occur is expected to undergo rearrangement of histone marks within individual genomic compartments and deregulated transcriptional program segmentation ( Sabi, 2024 ).

Sensors of DNA damage: Truncations of mutations in ATM (ATM serine/threonine kinase) and in the DNA mismatch repair (MMR) pathway (e. g., MLH1, MSH2, MSH6 genes) are mainly found in ATCs ( Zhang et al. , 2023 ). DNA repair deficiency presumably permits ATCs to become more genome unstable and to accumulate genomic dysfunctions, as described in other tumors, but the precise contributions of these changes to thyroid cancer progression are not yet functionally dissectable ( Arczewska et al. , 2026 ). Notably, a comparative study of thyroid cancer cell lines revealed that FTC133 and T243, which harbor truncating mutations in MMR genes, had a larger tumor burden than intact cells. That microsatellite instability was observed through STR profiling. Anecdotal data from multiple patient cohorts indicate that ATCs harboring MMR defects have a high mutational load ( Eng et al. , 2023 ).

Deregulation of mRNA splicing: Mutations in RBM10 are overrepresented in metastatic PTCs. It is also reported that de novo mutations in RBM genes occur in thyroid cancer cells resistant to vemurafenib, and their loss triggers splicing alterations that enhance extracellular matrix remodeling and improve metastatic potential ( Park et al. , 2022a ).

MAPK pathway: The MAPK pathway is frequently dysregulated in thyroid cancer, particularly in PTC. In most cases, alterations include activating mutations in RAS genes or the BRAF proto-oncogene, which alter upstream receptor signaling and return signal transduction through the MAPK pathway ( Table 1 ) ( Schubert et al. , 2023 ). BRAF mutations represent an early tumorigenic event in PTC, occurring in approximately 40-80% of cases, and are also detected in poorly differentiated thyroid carcinoma (PDTC; 5-35%) and anaplastic thyroid carcinoma (ATC; 10-50%) ( Min and Parameswaran, 2022 ). The most common alteration is the BRAF^V600E substitution, present in about 45% of PTCs, which results in constitutive kinase activation. Less common mutations near codon 600, such as K601E, exhibit comparatively lower oncogenic potential. In addition, BRAF fusions have been identified, particularly in radiation-associated PTCs ( Pupin et al. , 2025 ). The AKAP9BRAF rearrangement, which is identified in about 10% of radiation-induced PTCs, creates a fusion protein that has lost the N-terminal autoinhibitory domain, and this results in the activation of the kinase. Collectively, these alterations establish MAPK pathway hyperactivation as a central driver of thyroid tumor initiation, dedifferentiation, and disease progression ( Fig. 1 ) ( Darabi et al. , 2024 ).

Alterations in the TP53 pathway: TP53 is a transcription factor that acts as a tumor suppressor and influences the cell cycle and apoptosis. More than 75% of the mutations of TP53 consist of small changes in the DNA that result in the inactivation of the functions of the protein. The majority of the changes occur in the DNA-binding domain (92-292) ( Ueda et al. , 2022 ). With high percentages of PDTCs (10-35%) and ATCs (40-80%) containing TP53 mutations, it is thought that TP53 inactivation occurs late in tumor progression. In fact, mutations in tumor suppressors such as p53 and activating mutations in oncogenes such as RAS and BRAF ( Table 1 ) are responsible for the rapid proliferation and more aggressive form of thyroid cancer ( Schipor et al. , 2025 ).

Alterations in the TERT pathway: Most thyroid tumorigenesis is facilitated by activating mutations in the TERT ( Fig. 2 ). In addition, these mutations are more frequent in PDTCs (40%) and even more so in ATCs (70%). In contrast, their presence in PTCs and FTCs is relatively scarce, 10% and 20%, respectively, and in these settings, the prognosis is not as favorable ( Table 1 ) ( Liu et al. , 2025 ). Two mutually exclusive TERT promoter mutations are found in thyroid cancer: c228t (-124) and c250t (-146), both of which occur upstream of the TERT translation start site. Both mutations create a consensus binding site for the E-twenty-six (ETS) transcription factors in the TERT promoter, thereby enhancing TERT transcriptional activity. Finally, oncogene TERT mutations may co-occur with BRAF and RAS mutations in PDTCs and ATCs ( Fig. 2 ) ( Park et al. , 2022b ).

EFFECT OF TCM ON THE PATHOLOGICAL MECHANISM OF THYROID CANCER

Recent studies show that the effects of TCM may be manifested through modulation of several elements of the TME, regulation of immune responses, and modulation of the metabolic program ( He et al. , 2022 ). It can also act as a crosstalk hub for pathways involved in signals that lead to tumor proliferation, invasion, angiogenesis, metastasis, and therapeutic resistance ( Cheng et al. , 2024 ).

Regulation of MAPK and PI3K/Akt/mTOR

Dysregulation of the MAPK and PI3K/Akt/mTOR signal transduction pathways is a fundamental cancer-causing mechanism, especially in thyroid cancers with BRAF gene alterations. Increasing evidence indicates that bioactive compounds in TCM can prevent hyperphosphorylation in these signaling cascades, thereby inhibiting proliferative signaling and promoting therapeutic sensitivity ( Yan et al. , 2025 ). These agents target ERK1/2, Akt, and mTOR, resulting in downregulation of cyclin D1 and c-Myc and disruption of G1/S progression. In BRAF-driven models, certain compounds partially reverse constitutive MAPK activation by targeting BRAF/MEK signaling or restoring feedback control, resulting in decreased tumor growth and improved responsiveness to targeted therapies. Active compounds of anticancer TCMs exert their anticancer activity primarily by inhibiting the PI3K/Akt/mTOR pathway ( Carnazza et al. , 2025 ).

Prunellae Spica (the fruiting spike of Prunella vulgaris ) and its bioactive flavonoid, luteolin, have demonstrated significant potential to attenuate disease progression by targeting key intracellular signaling pathways ( Pan et al. , 2022 ). Mechanistic studies show that luteolin modulates both PI3K/Akt and NRF2/HO-1 signaling cascades, which play central roles in immune activation and oxidative stress responses ( Table 2 ). Inhibition of aberrant PI3K/Akt signaling reduces lymphocyte activation and inflammatory mediator production. In contrast, activation of the NRF2/HO-1 axis enhances cellular antioxidant defenses and mitigates reactive oxygen species–mediated tissue damage ( Wei et al. , 2025 ). Importantly, this dual regulatory effect promotes restoration of immune homeostasis by rebalancing the ratio of follicular helper T (Tfh) cells to follicular regulatory T (Tfr) cells, thereby limiting autoantibody production and reducing oxidative stress–associated thyroid injury ( Guo et al. , 2025 ).

Regulation of NF-κB and inflammatory networks

NF-κB activation of the Rel-domain transcription factors RelA, RelB, c-Rel, NF-KB1/p50, and NF-KB2/p52 is central to tumorigenesis and chemoresistance. NF-kB was shown to be aberrantly expressed in the majority of cancerous cells, and the kinases that block inhibitor of kappa B (IκB) are well-known important mediators of the NF-kB pathway ( Zhao et al. , 2025 ). NF-κB activation is closely linked to chemotherapy-mediated resistance, and suppressing NF-κB activation would sensitize cancer cells to chemotherapeutic agents, thereby enhancing their anticancer effects in cancer treatment ( Wang et al. , 2025 ). Extracts from Cortex Lycii Radicis (CLR), including triptolide (TP), minnelide, RA-XII, rubiarbonol G, wogonin, baicalein, and baicalin, are active compounds proven to induce apoptosis primarily via NF-κB signaling pathways in several cancers ( Fig. 2 ) ( Wang et al. , 2025 ).

Tripterygium wilfordii Hook. f. (Celastraceae) ( Table 2 ) was sustained from use in TCM as a treatment of cancer, and TP, one of many diterpenoid triepoxides, is the major bioactive compound extracted from the plant. Celastrol and TP are two bioactive diterpenoids in this herb with strong anticancer effects in thyroid carcinoma, due to their cyclic inhibition of NF-κB-mediated inflammatory networks ( Shan et al. , 2023 ). Celastrol suppresses the phosphorylation and degradation of I-κB, halting the decline in pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β, by preventing the nuclear translocation of NF-κB ( Table 2 ) ( Li et al. , 2025b ). It also inhibits IL-17 and TNF signaling and destabilizes inflammatory cascades that drive tumor cell proliferation, survival, and immune evasion. TP also augments these effects, and the combination of TP with the Hsp90 inhibitor BIIB021 has been shown to exhibit enhanced anticancer effects in thyroid carcinoma cells by amplifying inhibition of the NF-κB signaling pathway. Collectively, these mechanisms weaken inflammatory crosstalk and anti-survival signaling, facilitate apoptosis, and prevent progression of papillary thyroid carcinoma ( Tong et al. , 2022 ).

Apoptosis and cell death programs

A major anticancer effect of TCM-derived bioactive compounds is their induction of programmed cell death, most of which trigger intrinsic apoptosis by regulating mitochondrial signaling pathways and altering the Bax/Bcl-2 ratio ( Xiang et al. , 2024 ). An increase in pro-apoptotic Bax and a decrease in anti-apoptotic Bcl-2 disrupt mitochondrial membrane integrity, releasing cytochrome c and triggering caspase cascade activation, particularly caspase-9 and caspase-3, which cleave PARP and trigger execution. This mitochondrial-autonomous effect often occurs concomitantly with inhibition of pro-survival signaling, including Akt and NF-κB. It demonstrates the ability of TCM-derived compounds to act integratively, with multi-pathway anticancer effects, rather than solely to induce apoptosis ( Hai et al. , 2023 ).

Increasing evidence emphasizes the crosstalk between apoptosis and autophagy in response to TCM-derived molecules. Autophagy facilitates apoptosis in certain settings by amplifying mitochondrial impairment and augmenting ROS accumulation, whereas autophagy impedes tumor cells’ susceptibility to apoptosis. TCM bioactive compounds also trigger ferroptosis and other noncanonical cell death mechanisms involving lipid peroxidation, glutathione depletion, and GPX4 inhibition, thereby broadening the therapeutic power of TCM ( Huang et al. , 2023 ) . Prunella vulgaris (PV), hyperoside, rabdosia rubescens, and others are compounds mainly regulated by the Bcl-2/Bax pathway, and PV has been shown to trigger caspase-3 in thyroid cancer cells. The results indicate that TCM-derived compounds exploit autophagy, ferroptosis, and apoptosis to enhance cancer treatment and overcome treatment resistance ( Zhang et al. , 2022 ).

Evodia Rutaecarpa is widely used in TCM for the treatment of pain, aches, vomiting, and dysentery in China over the centuries ( Table 2 ). EVO (8,13,13b,14-tetrahydro-14-methylindolo[2’,3’:3,4]pyrido[2,1-b]quinazolin-5(7H)-one) is an alkaloid indole with a new structure produced through the extraction and isolation of E. rutaecarpa ( Luo et al. , 2026 ). EVO might significantly block cell proliferation and induce apoptosis by causing G2/M cell cycle arrest and by activating the apoptotic, cell cycle, and Wnt signaling pathways (MAPK and PI3K/Akt) in human ovarian cancer HO-8910PM cells. The inhibitory effect of EVO on cell proliferation and the induction of apoptosis in human ovarian A2780, A2780CP, ES-2, and SKOV-3 cells was also associated with activation of c-Jun N-terminal kinase (JNK) and protein kinase R-like endoplasmic reticulum kinase (PERK) ( Lin et al. , 2024 ). Further experiments revealed that EVO inhibits the growth of PTC and ATC cancer cells, and the cells undergo cellular death (apoptosis) in the presence of thyroid cancer EVO, and increases the effect of histone deacetylase inhibitors ( Zhen et al. , 2023 ). The influence of EVO on FTC has also been demonstrated in our previous research. Additionally, new EVO-based theranostic agents are being designed that combine fluorophores and tumor-targeting moieties to deliver drugs and visualize hypoxic tumors ( Yu et al. , 2024 ).

EMT and metastasis

EMT is a key cellular process that occurs during early embryogenesis and tissue differentiation, and it indicates a gradual shift away from epithelial cell characteristics towards mesenchymal features and the acquisition of stem-like properties ( Ge et al. , 2022 ). EMT is a stage in the process of solid tumor growth, invasion, metastasis, and therapy resistance. It plays a role in the transformation of low-grade to high-grade malignancy ( Ang et al. , 2023 ). Carcinoma cells undergo EMT as part of the TME developmental process and, consequently, to invade locally and metastasize to lymph nodes. Therefore, blocking signals involved in EMT has been shown to halt tumor progression in various human cancers ( Zhong and Sun, 2023 ).

In thyroid cancer, Curcuma longa plays an important role in regulating EMT and metastasis. It primarily exerts its action by inhibiting key signaling pathways, such as TGF-beta, which is pivotal in initiating EMT ( Table 2 ) ( Cao et al. , 2024 ). By inhibiting TGF-beta receptors and Smad proteins, curcumin prevents thyroid cancer cells from changing their phenotype from epithelial to mesenchymal and from becoming invasive and migratory. Additionally, curcumin suppresses EMT transcription factors like Snail, Twist, and Zeb1, which are essential for EMT induction. This action helps maintain the epithelial characteristics of cancer cells, thereby limiting their ability to spread ( Xu et al. , 2022 ).

Dong Quai has been observed to modulate autophagy in thyroid cancer cells by regulating the cell cycle and triggering apoptosis, thereby facilitating the clearance of damaged cellular components and promoting the degradation of malfunctioning organelles ( Table 2 ) ( Zhang et al. , 2025a ). Besides, Dong Quai prevents TGF-β-induced EMT by regulating major signaling cascades, especially the TGF-B/Smad pathway, which is implicated in cellular migration and invasion. Dong Quai inhibits this pathway, thereby preventing the conversion of epithelial cells into mesenchymal cells and suppressing the metastatic capabilities of thyroid cancer cells ( Li et al. , 2022a ).

Effects on the TME

The TME is the cellular and physical environment surrounding the primary tumor, including fibroblasts, endothelial cells, immune and inflammatory cells, components of the ECM, and soluble factors ( Yadav et al. , 2024 ). The TME enables intercellular communication between tumor and host cells, allowing tumor-promoting processes such as tumor angiogenesis, inflammation, and immune evasion ( Fig. 3 ) ( Rentschler et al. , 2022 ). The immune system, and its components in particular, have significant potential for cancer treatment, especially in modulating its activity. In the last decade, studies have shown that the outcome of immunotherapy can be influenced by various components of the TME, including the presence of immune cells before treatment ( Zhao et al. , 2023 ). Consequently, TCM agents exhibit promising therapeutic properties in immunotherapy, suggesting they may play a crucial role in modulating theTME ( Goenka et al. , 2023 ).

Immune regulation is one of the primary mechanisms by which TCM can modulate the TME. There are numerous TCM herbs, including Astragalus ( Astragalus membranaceus ) and Ginseng ( Panax ginseng ), which are known to boost immune cell activity, thereby increasing the body’s ability to identify and kill thyroid cancer cells ( Hu et al. , 2022 ). The herbs enhance anti-tumor immunity by enhancing natural killer (NK) cells and T cells. Moreover, some TCM herbs, such as Curcumin and Scutellaria baicalensis (Baikal Skullcap), regulate cytokines such as TNF-α and IL-6, which promote tumor growth and immune evasion. TCM can be used to create a less favorable TME by alleviating chronic inflammation ( Fig. 3 ) ( Su et al. , 2025a ).

Furthermore, herbs such as Reishi Mushroom ( Ganoderma lucidum ) have been shown to suppress angiogenic factors, including VEGF (vascular endothelial growth factor), thereby inhibiting the formation of new blood vessels within the TME ( Fu et al. , 2024 ). This reduces the tumor’s ability to thrive and metastasize by restricting its access to nutrients and oxygen. Moreover, another TCM-derived compound, Matrine, has shown promise in treating PTC in TPC-1 human cells ( Chen et al. , 2024 ). Research shows that the antithyroid cancer effects of matrine may be mediated by the miR-21/PTEN/Akt pathway, underscoring the importance of TCM in inducing apoptosis and arresting the cell cycle of thyroid cancer cells. This evidence highlights the importance of integrating TCM principles into the therapeutic environment for thyroid cancer, offering new treatment options and potentially benefiting patients ( Table 3 ) ( Li et al. , 2025c ).

DNA methylation and demethylation

DNA methylation and demethylation have been implicated in the pathogenesis and development of thyroid cancer, and some compounds in TCM have shown potential to modulate these processes ( Zang et al. , 2023 ). Another important epigenetic modification involved in gene expression regulation, DNA methylation, involves the cytosine ring being methylated at the 5th position ( Cortes et al. , 2022 ). In thyroid cancer, aberrant DNA methylation silences tumor suppressor genes and activates oncogenes that promote tumor growth and metastasis ( Sergeeva et al. , 2023 ).

Recent research studies have identified TCM-derived phytochemicals that can regulate DNMT (DNA methyltransferase) activity, which adds a methyl group to DNA. For example, a widely used TCM compound, curcumin, has been shown to reduce DNA methylation and DNMT1 levels in breast cancer cells, and its impact on the ras-association domain family protein 1A gene promoter results in re-expression of the gene ( Shahrajabian et al. , 2023 ). Also, resveratrol exerts greater effects on DNA methylation, decreasing the activity and expression of DNMT1, DNMT3A, and DNMT3B in numerous cancer types, including thyroid cancer. Alterations in these patterns of DNA methylation can disrupt the expression of cancer-regulating genes, possibly reinstating silenced tumor suppressor genes or silencing oncogenes, thereby altering the TME to suppress cancer development ( Song et al. , 2026 ). Another TCM, berberine, can suppress the expression of DNMT1 and DNMT3B, leading to hypomethylation of p53 and altering its signaling pathway, thereby enabling cell apoptosis in thyroid cancer ( Liu et al. , 2025 ).

Histone modification

Histone modifications are important for regulating gene expression, chromatin structure, DNA condensation, and the recruitment of effector molecules to modulate downstream gene expression. These changes can be either activating or suppressive to gene expression by either activating or repressing gene expression through methylation, acetylation, phosphorylation, ubiquitylation, and sumoylation ( Feng and Meng, 2022 ). In thyroid cancer, like in most other cancers, histone alterations that are abnormal cause aberrant expression of genes that relate to cancer, and this facilitates the growth and proliferation of tumors. For example, histone methylation may silence tumor suppressor genes, whereas histone acetylation is linked to transcriptional activation ( Singh et al. , 2018 ). Furthermore, the implication of histone modifications in gene regulation, and the introduction of normal histone modification patterns, is a major treatment process used in cancer therapy to reexpress tumor suppressor genes and suppress oncogene expression ( Li et al. , 2025a ).

Research has shown that TCM-derived compounds can alter histone modifications, which can be used to treat thyroid cancer. Curcumin is a well-known natural compound that can reduce EZH2 subunit expression in multiple cancer cells, including thyroid cancer ( Perna et al. , 2018 ). EZH2 also methylates histones and plays a key role in silencing tumor suppressor genes ( Liang et al. , 2021 ).

One of the most-researched posttranslational modifications is histone acetylation, which is involved in gene transcription activation. Two antagonistic families of enzymes regulate this: histone acetyltransferases (HATs) and histone deacetylases (HDACs), which deacetylate histones, promote DNA condensation, and cause gene silencing ( Wei et al. , 2022 ). The activity of HDAC is dysregulated in most cancers, such as thyroid cancer. Dysregulated HDAC activity results in the silencing of tumor suppressor genes and the activation of oncogenes. Curcumin, resveratrol, and berberine are TCM compounds that have been shown to be pan-HDAC inhibitors, capable of tuning HDAC activity to induce histone hyperacetylation ( Spartalis et al. , 2021 ). It may result in the re-reliance on tumor suppressor genes such as p53, p21, and PTEN, which promote cell cycle arrest, apoptosis, and diminished tumor proliferation in thyroid cancer. These TCM compounds, which can restore the balance between acetylation and deacetylation, have the potential to serve as adjunct treatments for epigenetic cancers ( Fig. 4 ) ( Yang et al. , 2025 ).

Noncoding RNA regulation in Thyroid cancer and TCM

Noncoding RNAs, such as microRNAs (miRNAs), are important in posttranscriptional regulation of gene expression in mammalian cells ( Xu et al. , 2024 ). Dysregulation of these noncoding RNAs has been found in thyroid cancer, which has been involved in the initiation, metastasis, and resistance of cancer to therapy. As small RNA molecules (20-22 nucleotides long), the microRNAs (miRNAs) regulate the target mRNA gene expression by binding to the 3 uttermost translation regions (UTRs) of their target mRNA, hindering its translation ( Qi et al. , 2022 ). Some miRNAs in thyroid cancer, including miR-34a, have been shown to be the main regulators of the p53 pathway, which affects cell growth, cell arrest, and apoptosis. The TCM therapies curcumin and resveratrol have been reported to modulate miRNA expression. For example, curcumin controls the EZH2-miR-101 feedback loop in multiple myeloma, triggering apoptosis, and resveratrol boosts immunity by altering miR-17 in breast cancer ( Wang et al. , 2024 ).

Also, lncRNAs (Longer than 200 nucleotides) have been reported in thyroid cancer, where they mediate tumor progression and chemoresistance, and EMT. An example of lncRNA, PVT1, is suppressed by curcumin and sensitizes cancer cells to therapy. Curcumin also suppresses LncRNA H19 expression; consequently, it increases p53 levels and induces apoptosis in cancer cells ( Li et al. , 2022c ). Other TCM compounds that regulate lncRNA expression include resveratrol and berberine; berberine has been shown to shift the expression levels of 538 lncRNAs in cancer cells. Even though the role of lncRNAs in treating thyroid cancer with TCM itself is being explored, their role in controlling cancer progression and responses to treatment is evident ( Zhu et al. , 2022a ). Overall, the role of TCM in regulating miRNA and lncRNA is a promising approach for treating thyroid cancer by restoring epigenetic balance, regulating tumor suppressor gene activity, and enhancing treatment effectiveness. Furthermore, these findings indicate that TCM-derived compounds modulate multiple oncogenic and epigenetic pathways involved in thyroid cancer progression, including PI3K/Akt/mTOR, NF-κB, TGF-β/Smad, and apoptosis-related signaling networks, as summarized in Fig. 5 .

CLINICAL EVIDENCE OF THYROID CANCER TREATED BY TCM

Topical use of TCM as a non-pharmacological form of therapy in the treatment of thyroid cancer has gradually gained more interest, especially regarding its ability to alleviate symptoms and improve quality of life ( Zhang et al. , 2025c ). TCM monotherapy usually follows syndrome differentiation, with treatment programs aimed at internal disequilibrium, including phlegm-qi stagnation and blood stasis, which, in the TCM model, are said to cause the pathogenesis of neck masses ( Ye and Chen, 2025 ).

The symptoms of the TCM syndrome are anterior neck swelling, swallowing movement, fullness at the anterior of the neck, difficulty in taking a breath, impaired swallowing, feeling of phlegm in the throat, unfavorable feeling in the throat and chest, abdominal pain, as per the guidelines of Clinical Research of New TCM (Trial). The symptoms are graded from 0 to 3, with 0 indicating no symptoms, 1 mild symptoms, 2 moderate symptoms, and 3 severe symptoms ( Yu et al. , 2023 ).

Lee et al. (2022) conducted a trial on the effectiveness and safety of the use of acupuncture as a method of anorexia treatment in patients with thyroid cancer with the addition of radioactive iodine (RAI). This was a randomized, blinded, sham-controlled pilot study; only 14 patients were randomly assigned to receive either true or sham acupuncture for 2 weeks. Both groups showed improvement, but the actual acupuncture group showed statistically significant changes in the quality-of-life sub-scales of the Trial Outcome Index (TOI), the Functional Assessment of Cancer Therapy-General (FACT-G), and the Functional Assessment of Anorexia and Cachexia Therapy (FAACT) ( p <0.05). It is noteworthy that no serious side effects were reported, and it is precisely a testament to the effectiveness of acupuncture as an alternative or self-treatment available to reduce the side effects of RAI.

A systematic review of 5,834 randomized controlled trials on cancer-related therapies found that approximately 18.55% used TCM monotherapy to treat symptoms and side effects. Within this category, some studies evaluated the palliative effectiveness of TCM in enhancing day-to-day functioning and reducing symptom burden in thyroid cancer, yielding initial results supporting the validity of TCM. Despite these positive results, several shortcomings should be noted. Most published clinical trials on TCM monotherapy for thyroid cancer are limited in sample size, center-specific, and vary in methodological quality. These aspects undermine the generalizability and reproducibility of results. Large-scale, high-quality, multicenter clinical trials with strict randomized, controlled designs to establish the clinical efficacy and long-term safety of TCM monotherapy in the management of thyroid cancer continue to burn ( Lu et al. , 2021 ).

CLINICAL EFFECT OF INTEGRATED TRADITIONAL CHINESE AND WESTERN MEDICINE IN THE TREATMENT OF THYROID CANCER

Clinical trials have shown that herbal decoctions, alone or combined with Eastern medicine, are effective in reducing the final diameter of TNs. Among the possible treatment methods, one can select standalone TCM, TCM and Western medicine combined, topical TCM, or internal and external TCM ( Cheng et al. , 2024 ). Clinical efficacy of TCM and Western medicine in treating TNs is thought to be their treatment response rate, nodule diameter, thyroid volume, FT3, FT4, TSH, TCM syndrome score, transforming growth factor (TGF-a), VEGF, interferon-gamma (IFN-γ), malignant transformation, and interleukins (IL) ( Table 3 ) ( Zhang et al. , 2025b ).

The synergistic approach of combining TCM and Western medical practice to treat thyroid cancer has become a popular trend in clinical practice, with good clinical results. They did the study on 120 patients who were discovered to have thyroid cancer, half of whom were placed in the experimental group; these patients were given a combination of total thyroidectomy and radioactive iodine, and the other half of the sample was placed into the control group, where the patients only underwent total thyroidectomy. The findings indicated that the overall efficacy rate in the experimental group was higher than in the control group. Moreover, the quality-of-life measures revealed that the experimental group scored much higher on the dimensions of physiological functioning, psychological functioning, social functioning, and general quality of life than the control group ( Yin et al. , 2018 ).

In addition, a research study specifically focused on benign thyroid nodules found a higher efficacy rate for TCM and Western medicine. The post-treatment assessment showed reductions in maximum nodule diameter and thyroid volume, as well as in free triiodothyronine (FT3), free thyroxine (FT4), and TSH secretion levels. In addition, TCM syndromes are scored lower. The above studies, taken together, indicate that implementing a hybrid approach combining traditional Chinese and Western medical interventions can enhance therapeutic outcomes in thyroid cancer and improve patients’ quality of life ( Zhu et al. , 2022b ).

Roth et al. (2018) noted that Yi Qi San Jie Tang, combined with levothyroxine sodium tablets, led to a striking reduction in nodule area during the 6 weeks of treatment. There was a significant decrease in nodule area at 12 weeks in the combination group compared with Western medicine and TCNG. There was also a significant reduction in the degree of TCM syndrome in both the combination group before and after treatment.

CHALLENGES IN THE TREATMENT OF THYROID CANCER WITH TCM

TCM formulations containing safety and effectiveness in thyroid cancer management are open to debate. Although the negative outcomes of using TCM are not too much, some formulations can cause adverse reactions, such as hepatotoxicity, nephrotoxicity, and allergic reactions ( Chen et al. , 2023b ; Li et al. , 2022b ). As an illustration, renal impairment has been associated with TCMs based on aristolochic acid. Additionally, several factors can affect the quality of TCM therapy, such as the origin of the ingredients and their preparation, and the quality may be inconsistent, thereby affecting effectiveness and safety ( Zhongyuan, 2022 ).

Regarding efficacy, some clinical studies indicate that TCM may play a role in reducing symptoms and improving the quality of life of thyroid cancer patients ( Zhang and Xiao, 2021 ). Small sample sizes and methodological constraints have characterized many studies, rendering their findings unreliable and inconclusive. Furthermore, the mechanism by which TCM exerts its action in the management of thyroid cancer is still not well understood, which further impedes its widespread use in clinical practice ( Zhang et al. , 2026a ).

Furthermore, TCM-based treatment patterns, which are based on the differentiation of syndromes, do not follow standardized guidelines, which means there may be differences in the treatment regimen given by a practitioner working on the same patient. There is also no consistency in the duration and dosages of TCM used to treat thyroid cancer, with most practitioners usually basing their practice on trial and error to develop treatment regimens ( Veleber et al. , 2024 ). Moreover, the new drug research and development approval process within TCM is particularly complicated, and there is a lack of established evaluation criteria that address the peculiarities of TCM ( Jiang and Bu, 2024 ).

FUTURE DIRECTIONS

Recent developments in TCM formulations have identified promising opportunities for their application in treating thyroid cancer ( Zheng et al. , 2018 ). New technologies, such as nanoformulations, liposomes, and microspheres, have been developed to enhance the bioavailability and targeted delivery of bioactive compounds in TCM ( Qiu et al. , 2023 ). These inventions enable changing the TCM ingredients to smaller particle sizes that enhance the accumulation of the drugs in tumor tissues whilst reducing harm to the healthy cells around them ( Zheng et al. , 2022 ). The potential of these high-tech preparations is evident in their ability to prevent the proliferation of thyroid cancer cells, induce their apoptosis, block angiogenesis, and alter immune status. Nonetheless, their effectiveness and safety in the treatment of thyroid cancer, as well as these new formulations, should be validated in clinical trials, since the subject remains largely experimental ( Kang et al. , 2023 ).

Modern technology integration with TCM has shown promising prospects, especially in nanotechnology. Nanocarriers will allow targeted delivery of active components in TCM to thyroid tumor cells, increasing cytotoxicity against the tumor cells and decreasing damage to normal tissues ( Sun et al. , 2025 ). Also, network pharmacology and bioinformatics are being used to elucidate the molecular interactions between TCM components and thyroid cancer-associated targets, thereby enabling the discovery of novel anticancer agents. Further studies can also capture the power of Artificial Intelligence (AI) to clarify the distinction between TCM syndromes and treatment modalities, resulting in increasingly accurate, tailored therapies for thyroid cancer ( Kumari et al. , 2022 ).

In the future, the use of gene-editing strategies, including CRISPR-Cas9, will likely be instrumental in improving the efficacy of TCM in the treatment of thyroid cancer ( Su et al. , 2025b ). The genetic regulation of thyroid cancer can be studied using CRISPR, and changes in TCM in relation to specific genes involved in tumorigenesis can provide useful information for targeted therapy ( Zhu et al. , 2025 ). In addition, the combination of stem cell therapy and TCM could ameliorate tissue repair and regulate immune responses, thereby improving the overall treatment outcome ( Sembiyaa et al. , 2025 ).

The overlap between AI and Systems Biology shows great potential to nurture TCM in managing thyroid cancer. It is expected that, with the development of AI technology, they will become capable of handling and analyzing multi-omics data, such as genomic, transcriptomic, proteomic, and metabolomic datasets, and identifying complex patterns in cancer biology as this information becomes available in large quantities ( Zhang et al. , 2024 ). In the future, AI will be used to tailor treatment regimens by incorporating TCM compounds based on a patient’s unique molecular profile, thereby enhancing efficacy and reducing side effects ( Guicheng et al. , 2025 ). Nanoformulations will also be developed further using AI algorithms, as TCM compounds will be delivered with greater precision to tumor tissues, particularly in thyroid cancer cells. This represents a shift towards precision medicine, where AI optimizes and tailors treatments based on patient-specific data ( Zhang et al. , 2026b ).

The Systems Biology approach, with its systems-level perspective, will be essential for elucidating the underlying molecular networks driving thyroid cancer progression and treatment resistance ( Cui et al. , 2025 ). Multi-omics profiling, driven by systems biology in the future, will aid in the identification of new biomarkers to detect thyroid cancer and determine how TCM impacts cancer pathways. The combination of systems biology models with AI will enable researchers to develop predictive models that replicate thyroid cancer behavior at the cellular and molecular levels, predicting how various TCM approaches will interact with different populations of cancer cells ( Gan et al. , 2025 ). Hence, the field of AI keeps evolving; it is likely to assist in filling the gap between preclinical research and clinical practice, enabling real-time patient monitoring and adjusting therapy to achieve maximum effectiveness.

CONCLUSION

The treatment of thyroid cancer remains challenging due to its molecular heterogeneity, recurrence, and resistance to conventional therapies. TCM, with its rich history and diverse bioactive compounds, offers a promising adjunctive or alternative platform for overcoming these challenges. These compounds have demonstrated promise in controlling the TME, decreasing immunogenicity, and increasing the sensitivity to therapies. TCM acts by suppressing tumor cell growth, inducing apoptosis, inhibiting tumor cell metastasis, and modulating tumor cell survival and metastasis-associated signaling and pathways. Additionally, the combination of new TCM formulations, AI, and systems biology offers many opportunities to develop precision medicine, enabling targeted therapies and enhancing patient outcomes. AI may benefit the identification of molecular targets and the development of individualized TCM-based therapies, and systems biology offers a comprehensive view of cancer biology to support treatment optimization. Furthermore, gene editing and stem cell therapies can be added to complement such developments, providing customized therapeutic approaches. Nonetheless, additional large-scale multicenter clinical trials are needed to demonstrate the safety and effectiveness of TCM in treating thyroid cancer. Finally, the meeting point of TCM and modern scientific technologies holds a bright future for the integrative treatment of cancer, increased efficiency, personalization, and less-toxic treatment for thyroid cancer patients.

ACKNOWLEDGMENTS

This work is supported by The Jilin Scientific and Technological Development Program (No:YDZJ202401115ZYTS).

CONFLICT OF INTEREST

The authors declare that there is no conflict of interest.

AUTHOR CONTRIBUTIONS

Yuzhuo Bai, Ke Feng, Xiaojiang Li, Xiuli Xing, Zhiyuan Zhang, Bingsen Wang, and Ying Liu conceived, performed the overall literature search, interpreted, analyzed, and validated the data and wrote the manuscript. Ying Liu supervised the study. All authors reviewed the manuscript.

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