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. 2026 Sep 5;18:635801. doi: 10.2147/CMAR.S635801

Thyroid Cancer in the Modern Era: From Molecular Landscape and Multimodal Diagnostics to Integrative Traditional Chinese Medicine—A Comprehensive Review

Yingqi Xiong 1, Yaxin Hu 2, Manya Wang 3, Xin Xiong 4,✉, Haishen Zhao 3,✉
PMCID: PMC13557154  PMID: 42719379

Abstract

In recent decades, the global incidence of thyroid cancer has risen sharply mainly due to the high detection rate of papillary thyroid microcarcinoma and overdiagnosis, with its overall mortality staying steady. Classic pathogenic drivers encompass childhood radiation exposure, iodine disorder, and hallmark gene alterations including BRAF V600E, RET/PTC, RAS and PAX8/PPARγ. Modern multimodal diagnostic systems integrating artificial intelligence-assisted high-resolution ultrasound, Thyroseq-V2, Afirma, circulating tumor DNA detection and refined pathological examination achieve precise preoperative stratification. Aberrant activation of MAPK/ERK, PI3K/AKT and Wnt/β-catenin cascades, coupled with an immune-suppressive tumor microenvironment dominated by M2-type tumor-associated macrophages, regulatory T cells and PD-L1 overexpression, drives thyroid cancer progression and dedifferentiation. Current comprehensive integrated therapeutic strategies cover robotic surgery, radioactive iodine ablation, external radiotherapy, molecular targeted drugs (sorafenib, lenvatinib, vemurafenib combined with trametinib) and novel immunotherapy. Traditional Chinese Medicine (TCM), based on the TCM pathogenesis of liver qi stagnation, phlegm-blood stasis and qi-blood deficiency for goiter, serves as an adjuvant therapy for thyroid cancer. Active ingredients such as honokiol, artesunate, ginsenoside Rg3, astragalus polysaccharide and curcumin can suppress tumor proliferation, reshape anti-tumor immunity and inhibit metastasis via regulating reactive oxygen species, PI3K/AKT pathway, epithelial–mesenchymal transition and matrix metalloproteinases. Existing clinical observations confirm that TCM can relieve clinical discomfort, improve life quality and lower recurrence risk when combined with conventional radioiodine or anti-tumor treatment. However, the clinical application of TCM for thyroid cancer is greatly restricted by insufficient syndrome differentiation standardization, low-quality clinical evidence and unclear herbal safety risks. Most available studies are small-sample retrospective analyses lacking large-scale, multicenter randomized controlled trials to verify efficacy and safety. Future research should focus on standardized clinical trial design, in-depth pharmacological mechanism exploration, and construction of standardized thyroid cancer integrative diagnosis and treatment regimens combining Western precision therapy and TCM adjuvant intervention, to clarify the definite positioning of TCM in whole-course thyroid cancer management.

Keywords: thyroid cancer, BRAF V600E, tumor microenvironment, targeted therapy, traditional Chinese medicine, immunomodulation, overdiagnosis, multimodal imaging

Introduction

Thyroid cancer is the most prevalent malignancy within the endocrine system, and its global incidence has increased three- to fourfold over the past 40 years. This increase is largely attributable to the enhanced detection of papillary thyroid microcarcinomas; however, disease-specific mortality rates have not increased proportionally, strongly indicating the presence of overdiagnosis.1,2 The disease demonstrates a marked female predominance and is increasingly being identified in younger individuals. Established risk factors include exposure to ionizing radiation, particularly during childhood, inherited syndromes such as multiple endocrine neoplasia type 2, and abnormalities in iodine intake.3,4 Beyond oncological resection, endocrine surgical procedures can induce postoperative biochemical and metabolic disturbances that profoundly affect long-term patient prognosis and quality of life. A recent prospective clinical study by Şahin et al systematically characterized postoperative fluctuations in key nutritional and metabolic biomarkers, including vitamin B12, folate, and homocysteine, in patients undergoing endocrine-related metabolic surgery, highlighting the essential role of routine long-term biochemical surveillance in optimizing postoperative endocrine patient management.5 Although this investigation focuses on bariatric metabolic surgery rather than thyroidectomy, its emphasis on postoperative metabolic homeostasis and targeted biochemical monitoring provides generalized, up-to-date evidence for standardized postoperative care across endocrine surgical disciplines, further enriching the clinical background of thyroid cancer perioperative management.

At the molecular level, tumor initiation and progression are driven by the constitutive activation of the MAPK/ERK and PI3K/AKT signaling pathways through mutually exclusive genetic alterations, including BRAF V600E mutations (observed in 50–70% of papillary thyroid cancers), RAS mutations, RET/PTC rearrangements, and PAX8/PPARγ fusions. Additionally, mutations in the TERT promoter are associated with aggressive tumor phenotypes.6,7 The tumor immune microenvironment, characterized by M2-polarized tumor-associated macrophages, infiltration of regulatory T cells, and upregulation of PD-L1, contributes to immune evasion and dedifferentiation, particularly in anaplastic thyroid carcinoma.8

Recent advancements in diagnostic modalities, such as high-resolution ultrasonography, molecular classifiers (eg, ThyroSeq-V2, Afirma), and liquid biopsy techniques, have significantly improved preoperative risk stratification.9 Therapeutic approaches have evolved beyond surgery and radioactive iodine therapy to include multikinase inhibitors (such as sorafenib and lenvatinib), targeted BRAF/MEK inhibitors, and immune checkpoint blockade in refractory cases.10

Concurrently, Traditional Chinese Medicine (TCM), grounded in the ancient concept of “ying disease” and employing pattern-differentiated formulations aimed at harmonizing liver qi, resolving phlegm, and promoting blood circulation, has attracted growing interest as a complementary therapeutic strategy. Contemporary pharmacological investigations have demonstrated that TCM-derived compounds, including honokiol, artesunate, ginsenoside Rg3, astragalus polysaccharide, and curcumin, exert antitumor effects by inhibiting cellular proliferation, inducing apoptosis, reversing epithelial–mesenchymal transition, and modulating the immunosuppressive tumor microenvironment.11,12

Despite these promising findings, the integration of TCM into thyroid cancer management faces significant challenges, such as variability in diagnostic criteria, scarcity of high-quality clinical evidence, potential herb-drug interactions, and unclear dose-response relationships. This review aims to comprehensively synthesize the current understanding of thyroid cancer epidemiology, molecular pathology, diagnostic imaging, molecular diagnostics, conventional treatment modalities, and mechanistic and clinical evidence supporting TCM integration. Furthermore, it critically examines existing controversies and outlines future directions for precision combination therapies.

Methods

Electronic databases including PubMed, Embase, Web of Science, CNKI and Wanfang Data were searched up to April 30, 2026 for literature published from January 2000 to April 2026 using a combined retrieval strategy of Medical Subject Headings and free-text terms: (thyroid carcinoma OR thyroid cancer) AND (multimodal diagnosis OR molecular detection OR surgical therapy OR targeted therapy OR immunotherapy) AND (Traditional Chinese Medicine OR Chinese herbal medicine OR adjuvant therapy); backward snowball searching of references in key reviews and forward citation tracking of core original articles were also performed to retrieve missed relevant papers, with predefined inclusion criteria covering eligible clinical trials, preclinical cell/animal studies and full-text Chinese/English reviews reporting TCM-related mechanism, efficacy or safety data for thyroid cancer, and exclusion criteria removing conference abstracts, single case reports, duplicate publications, irrelevant papers and studies with incomplete design and missing objective endpoints, all retrieved records being imported into EndNote for deduplication before two independent researchers conducted two-stage title/abstract and full-text screening, resolving discrepancies through group discussion and intentionally incorporating neutral, negative and conflicting outcomes during screening to reduce literature selection bias rather than only relying on positive results.

Epidemiology

The global incidence of thyroid cancer has increased markedly in recent decades, particularly in high-income nations. For instance, in Germany, the incidence rate is approximately seven cases per 100,000 individuals, with a notably higher prevalence observed among women than among men.1 In the United States, the incidence of thyroid cancer has quadrupled over the past 40 years, a trend predominantly driven by an increase in papillary thyroid cancer (PTC), especially papillary microcarcinoma (PTMC).2 Similarly, in Kerala, a southern state of India, the incidence of thyroid cancer increased by 93% between 2006 and 2012, with the age-adjusted incidence rate among women increasing from 6.9 to 13.3 per 100,000 population.5 This surge is largely attributed to overdiagnosis because mortality rates from thyroid cancer have not shown a corresponding increase. For example, in Russia, the incidence of thyroid cancer tripled among women and doubled among men between 1989 and 2015, whereas mortality rates remained stable.13 Furthermore, the age distribution of thyroid cancer cases tends to skew younger, particularly among women, a pattern potentially linked to environmental influences, lifestyle modifications, and advancements in diagnostic methodologies.14

Several risk factors for thyroid cancer have been identified, including exposure to radiation, genetic predispositions, abnormal iodine intake, and other environmental determinants. Radiation exposure, especially to the head and neck region during childhood, is a well-established risk factor that significantly increases the likelihood of developing thyroid cancer.15 For example, following the Fukushima nuclear disaster, extensive thyroid screening resulted in substantial overdiagnosis despite relatively low radiation exposure levels.16 Genetic factors also play a critical role in thyroid carcinogenesis; notably, the BRAF V600E mutation occurs in 50–70% of PTC cases and is significantly associated with bilateral tumor presentation.6 Familial thyroid cancer syndromes, such as multiple endocrine neoplasia type 2, further augment this risk. Abnormal iodine intake is also implicated, with iodine deficiency increasing the risk of follicular thyroid cancer (FTC), whereas excessive iodine intake may be linked to PTC.3 Additional environmental factors, including obesity, tobacco use, alcohol consumption, and exposure to certain chemicals, have been suggested to contribute to thyroid cancer development; however, the precise mechanisms remain to be elucidated.1

Epidemiological investigations have underscored the importance of genetic factors in the pathogenesis and progression of thyroid cancer. BRAF V600E mutation is the most prevalent driver mutation in PTC and correlates with increased tumor aggressiveness, recurrence risk, and poorer prognosis.6 Other common genetic alterations include RET/PTC rearrangements, RAS mutations, and PAX8/PPARγ fusions.17 These mutations are typically mutually exclusive, indicating distinct pathogenic pathways. For example, BRAF mutations predominantly occur in classical PTC, whereas RAS mutations are more frequently observed in FTC and the follicular variant of PTC.3 Genetic predisposition also influences familial clustering of thyroid cancer, with approximately 5–10% of patients reporting a family history and a higher familial incidence noted in medullary thyroid cancer (MTC).18 Genome-wide association studies (GWAS) have identified several susceptibility loci, including FOXE1 and NKX2-1, that may contribute to tumorigenesis by regulating thyroid development and function.4

Diagnosis

Imaging diagnosis of thyroid carcinoma predominantly relies on ultrasonography, with high-resolution ultrasonography (HRUS) being the preferred modality. HRUS enables a detailed assessment of nodule characteristics, including size, shape, margins, internal echogenicity, and calcifications.9 For instance, microcalcifications represent a significant ultrasonographic feature of PTC. The integration of 10–24 MHz high-frequency ultrasound with artificial intelligence (AI) demonstrated a microcalcification detection rate of 91.4%.9 Ultrasound elastography contributes to diagnostic accuracy by evaluating nodule stiffness; specifically, quantitative elasticity parameters such as maximum elasticity (Emax) ≥ 30.65 kPa, when combined with molecular markers such as vascular endothelial growth factor (VEGF) and programmed death-ligand 1 (PD-L1), can enhance diagnostic specificity to 93.6%.9 Contrast-enhanced ultrasound (CEUS) facilitates the evaluation of nodule vascular perfusion, aiding in differentiating between benign and malignant lesions.19 Furthermore, positron emission tomography/computed tomography (PET/CT) plays a critical role in diagnosing radioiodine-refractory thyroid cancer, and 18F-fluorodeoxyglucose (FDG) PET/CT effectively identifies metabolically active tumor tissue.20 The application of virtual reality (VR) enhancement technology in conjunction with CEUS has been shown to improve diagnostic accuracy and achieve sensitivity and specificity rates exceeding 85%.21

Molecular diagnostic approaches to thyroid cancer include gene mutation analysis, gene expression profiling, and circulating tumor DNA (ctDNA) detection. Molecular testing of fine-needle aspiration cytology (FNAC) specimens effectively addresses the challenges of indeterminate cytology. Frequently used genetic markers include BRAF, RAS, RET/PTC rearrangements, and PAX8/PPARγ fusions.22 Clinically validated assays such as ThyroSeq v2 and Afirma demonstrate differential predictive values, with the former exhibiting a higher positive predictive value and the latter exhibiting a higher negative predictive value.23 Gene expression classifiers (GECs) analyze gene expression patterns to distinguish benign from malignant nodules, achieving negative predictive values exceeding 95%.24 Additionally, non-coding RNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have emerged as diagnostic biomarkers; for example, miR-136, miR-21, and miR-127 are aberrantly expressed in PTC.25 As a minimally invasive modality, ctDNA analysis offers the potential for monitoring tumor recurrence and therapeutic response, although challenges related to assay standardization and sensitivity remain.26

The pathological diagnosis of thyroid cancer primarily depends on histopathological evaluation. According to the 2017 World Health Organization (WHO) classification, thyroid carcinomas are categorized into papillary, follicular, medullary, undifferentiated, and other subtypes.27 The eighth edition of the General Rules for the Description of Thyroid Cancer (GRDTC), developed by the Japanese Society of Thyroid Pathology and the Japanese Society of Endocrine Surgery, diverges from the WHO classification by excluding the concept of borderline lesions, such as follicular tumors of uncertain malignant potential (FT-UMP), well-differentiated tumor of uncertain malignant potential (WDT-UMP), and non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP).28 Immunohistochemical markers, including Galectin-3, Cytokeratin 19, and HBME-1, assist in distinguishing benign from malignant tumors, and their combined use enhances the diagnostic precision.29 Notably, Galectin-3 exhibits high expression rates and specificity in thyroid malignancies.30 Moreover, proliferation indices such as Ki-67 and tumor suppressor protein p53 expression serve as indicators of tumor aggressiveness; a Ki-67 labeling index exceeding 30% correlates with a poor prognosis.31 In follicular lesions, vascular invasion constitutes a critical criterion for malignancy, with stringent definitions, such as tumor cell penetration of the vessel wall and thrombus formation, predictive of distant metastasis.32

Pathophysiological Mechanisms

Cell Signaling Pathways

The initiation and progression of thyroid cancer are intricately linked to the dysregulated activation of multiple signaling pathways, with the MAPK/ERK, PI3K/AKT, and Wnt/β-catenin pathways being particularly pivotal.7 The MAPK/ERK pathway is predominantly activated through genetic alterations, such as BRAF mutations, RAS mutations, or RET/PTC rearrangements, leading to aberrant cellular proliferation and differentiation.31,33 Notably, the BRAF V600E mutation results in constitutive activation of the MAPK pathway, thereby facilitating PTC development.1,6 Similarly, activation of the PI3K/AKT pathway, often driven by PIK3CA mutations, PTEN loss, or RAS mutations, contributes to enhanced cell survival and invasiveness.34 Aberrant activation of the Wnt/β-catenin signaling cascade is frequently observed in ATC, where the nuclear accumulation of β-catenin correlates with tumor dedifferentiation.35 Furthermore, BRD9 has been identified as a promoter of thyroid cancer cell proliferation and invasion via the activation of the MAPK/ERK pathway.36 Importantly, these signaling pathways exhibit crosstalk, collectively orchestrating the malignant phenotype of thyroid cancer cells.37

Gene Mutation and Expression

Genetic alterations in thyroid cancer predominantly involve genes associated with the MAPK and PI3K/AKT signaling pathways. The BRAF V600E mutation is the most prevalent genetic alteration in PTC, with an occurrence rate of approximately 50–70%, and is correlated with increased risks of tumor bilaterality, invasiveness, and recurrence.6 Mutations in RAS genes, including HRAS, KRAS, and NRAS, are frequently observed in follicular variants of both FTC and PTC, with incidences ranging from 10% to 20%.17 RET/PTC rearrangements are predominantly identified in radiation-induced PTC cases, affecting about 10–20% of patients.3 Additionally, PAX8/PPARγ gene fusions are present in approximately 30% of FTC cases.17 Furthermore, mutations in the TERT promoter are commonly detected in thyroid cancers and are associated with increased tumor aggressiveness and poor clinical outcomes.4 Biomarkers such as Galectin-3, Cytokeratin 19, and VEGF exhibit elevated expression in thyroid cancer and serve as valuable diagnostic indicators.29

Study on Immune Microenvironment

The immune microenvironment of thyroid cancer comprises immune cells, cytokines, and the extracellular matrix, which collectively play critical roles in tumor initiation, progression, and therapeutic response.38 Tumor-associated macrophages (TAMs), predominantly of the M2 phenotype in thyroid cancer, facilitate tumor proliferation and invasion through cytokine secretion.39 The infiltration of regulatory T cells (Tregs) contributes to the suppression of antitumor immune responses and correlates with unfavorable clinical outcomes.40 Furthermore, tumor cells evade immune surveillance by expressing immune checkpoint molecules such as PD-L1.25 Spatial transcriptomic analyses have revealed upregulation of immunosuppressive gene expression within ATC regions, accompanied by an enrichment of TYMP-positive TAMs, thereby establishing an immunosuppressive microenvironment.8 The interaction between Annexin A1 and FPR1 may enhance the immunomodulatory functions of dendritic cells, subsequently promoting tumor progression.41 The immune microenvironment has potential as a prognostic biomarker and therapeutic target. For instance, elevated CXCL10 expression is associated with improved prognosis.42

Treatment

The surgical management of thyroid cancer primarily involves thyroidectomy and lymph node dissection. While conventional open thyroidectomy remains the standard approach, robot-assisted thyroidectomy techniques such as the bilateral axillary breast approach (BABA) offer advantages in terms of cosmetic outcomes and surgical precision.43 For patients with low-risk PTC, thyroid lobectomy may be adequate; however, total thyroidectomy is recommended for those classified as high-risk.44 The optimal extent of lymph node dissection remains a subject of debate, with the benefits of prophylactic central compartment lymph node dissection yet to be definitively established.45 Additionally, ultrasound-guided thermal ablation is a minimally invasive treatment option for low-risk papillary thyroid microcarcinoma (PTMC), although careful patient selection is imperative.46 Surgical complications, including recurrent laryngeal nerve injury and hypoparathyroidism, continue to pose challenges. Nonetheless, the implementation of intraoperative nerve monitoring and parathyroid preservation techniques has been shown to mitigate these risks.47

Radiotherapy interventions for thyroid cancer predominantly include radioiodine therapy (RAI) and external beam radiotherapy (EBRT). RAI serves as a critical adjuvant treatment for differentiated thyroid carcinoma (DTC), facilitating the ablation of residual thyroid tissue and management of metastatic disease.48 In cases where patients develop RAI-refractory disease, EBRT or targeted therapies are considered as appropriate alternatives.49 Brachytherapy employing 125I seed implantation has demonstrated efficacy in treating locally recurrent thyroid cancer and is typically administered at a prescribed dose of approximately 120 Gy, achieving high rates of local control.50 Emerging modalities, such as proton and heavy-ion radiotherapy, are under investigation for their potential to minimize collateral damage to normal tissues.51 Furthermore, radionuclide-labeled targeted agents, including 131I-metaiodobenzylguanidine (MIBG), have exhibited therapeutic potential for medullary thyroid carcinoma (MTC).52

Targeted therapeutic strategies for thyroid cancer predominantly target the MAPK, PI3K/AKT, and VEGF signaling pathways. Sorafenib and lenvatinib, both FDA-approved multi-targeted tyrosine kinase inhibitors (TKIs), have demonstrated efficacy in prolonging progression-free survival in patients with RAI-refractory DTC.53 Vandetanib and cabozantinib are employed in the management of advanced MTC and exert inhibitory effects on the RET and VEGF pathways.18 The combination of BRAF inhibitors (eg, dabrafenib) with MEK inhibitors (eg, trametinib) significantly extends survival in patients with BRAF-mutated anaplastic thyroid carcinoma (ATC).10 Immunotherapeutic approaches, particularly PD-1/PD-L1 inhibitors such as pembrolizumab, have shown promise in ATC and poorly differentiated thyroid carcinoma (PDTC), especially when used concomitantly with targeted therapies.54 Additionally, investigational modalities, including chimeric antigen receptor T-cell (CAR-T) therapy and tumor vaccines, are being explored for their potential applications in thyroid cancer treatment.55

Basic Theory of Thyroid Cancer Treated by TCM

Thyroid cancer is classified within the TCM framework as a type of “gall disease” Its etiology and pathogenesis are multifaceted and primarily associated with emotional disturbances, dietary irregularities, environmental factors such as water and soil quality, and physical influences. Emotional disorders including prolonged depression, anger, and anxiety are believed to cause stagnation of liver qi, disruption of qi circulation, abnormal fluid distribution, phlegm accumulation, and obstruction of phlegm and qi in the anterior neck region, leading to goiter formation. Persistent qi stagnation may transform into fire, which consumes bodily fluids, converts fluids into phlegm, or results in phlegm and blood stasis, thereby causing meridian obstruction and mass formation. Dietary factors such as chronic consumption of foods with either insufficient or excessive iodine can impair the transport and transformation functions of the spleen and stomach, leading to water retention, dampness accumulation, phlegm production, and entrapment of phlegm and qi in the neck, thereby contributing to disease onset. Additionally, congenital deficiencies, diminished vital qi, or acquired malnutrition can cause visceral dysfunction, impaired qi and blood circulation, and internal blood stasis, all of which are significant contributors to thyroid cancer development. Contemporary research corroborates that patients with thyroid cancer frequently exhibit syndromes characterized by liver depression, qi stagnation, phlegm, and blood stasis, aligning with TCM etiological and pathogenic theories.56

From a microscopic perspective, there is notable correspondence between TCM etiological concepts of TCM and the pathological mechanisms recognized in modern medicine. For instance, liver-qi stagnation induced by emotional disturbances may be linked to dysregulation of the neuroendocrine-immune network. Chronic psychological stress can disrupt the hypothalamic-pituitary-thyroid axis, resulting in abnormal secretion of thyroid hormones and aberrant proliferation of thyroid cells. Dietary iodine abnormalities are closely associated with thyroid cancer risk; iodine deficiency can provoke excessive proliferation of thyroid follicular epithelial cells, increasing cancer susceptibility, whereas excessive iodine intake may induce thyroid cancer through mechanisms involving oxidative stress and DNA damage.57 Furthermore, deficiency of vital qi corresponds to compromised immune function, wherein weakened immune surveillance permits tumor cells to evade immune detection, thereby facilitating tumor initiation and progression.58

The theoretical foundation of TCM treatment for thyroid cancer is grounded in its holistic philosophy and the principle of syndrome differentiation and treatment, emphasizing the dual approach of reinforcing body resistance and eliminating pathogenic factors. Strengthening vital qi encompasses strategies such as replenishing qi to invigorate the spleen, nourishing yin to tonify the kidney, and nourishing the blood to calm the mind, all aimed at enhancing the body’s healthy qi, bolstering immune function, and improving the patients’ physical condition. Pathogen elimination involves methods such as soothing the liver, regulating qi, resolving phlegm and masses, promoting blood circulation, removing blood stasis, clearing heat, and detoxification to eradicate tumor lesions and inhibit tumor growth. For example, in thyroid cancer patients exhibiting liver depression and qi stagnation, prescriptions that soothe the liver, regulate qi, and resolve phlegm and masses, such as Chaihu Shugan Powder and Haizao Yuhu Decoction, have been shown to effectively alleviate the symptoms of emotional distress and neck masses. For patients presenting with phlegm and blood stasis, formulations that promote blood circulation, remove blood stasis, and soften hard masses, such as the modified Taohong Siwu Decoction and Haizao Yuhu Decoction, can enhance local blood flow and inhibit tumor cell invasion and metastasis.56

Modern investigations have demonstrated that the theoretical underpinnings of TCM in thyroid cancer treatment intersect the molecular mechanisms identified in contemporary medicine. For instance, herbs that tonify qi and invigorate the spleen can enhance the activity of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) by modulating immune function, thereby improving the body’s capacity to eliminate tumor cells.58 TCM agents that resolve phlegm and masses have been found to inhibit tumor cell proliferation, induce apoptosis, and regulate the cell cycle.11 Additionally, herbs that promote blood circulation and remove blood stasis can impede tumor progression by improving the tumor microenvironment, inhibiting angiogenesis, and reducing metastasis.59 Moreover, TCM interventions can attenuate the proliferative effects of thyroid-stimulating hormone (TSH) on thyroid cancer cells by modulating endocrine function, including reducing TSH levels.57

Pathological Mechanism of Thyroid Cancer Treated by TCM

Mechanism of TCM on Proliferation of Thyroid Cancer Cell

TCM can inhibit the proliferation of thyroid cancer cells through multiple potential mechanisms observed in preclinical models. For instance, honokiol, a natural polyphenolic compound derived from Magnolia officinalis, has displayed antithyroid cancer activity in limited laboratory settings. Research indicates that Honokiol suppresses the proliferation of human undifferentiated thyroid cancer cell lines (KMH-2 and ASH-3) by promoting the generation of reactive oxygen species (ROS).11 This effect was mediated by ROS-induced cell cycle arrest and apoptosis in this single cell model. Furthermore, Honokiol impedes tumor cell migration and invasion by modulating the expression of markers associated with epithelial-mesenchymal transition (EMT) in vitro.11

Artesunate, a derivative of artemisinin, also exhibits antithyroid cancer activity. Studies have revealed that artesunate induces apoptosis in thyroid cancer cells while inhibiting their proliferation and migration by targeting the PI3K/AKT/FKHR signaling pathway. Specifically, artesunate reduces the phosphorylation levels of PI3K, AKT, and FKHR, upregulates pro-apoptotic proteins, such as caspase-3 and Bax, and downregulates the anti-apoptotic protein Bcl-2.12 Additionally, artesunate induces cell cycle arrest at the G0/G1 phase12 by suppressing the expression of Cyclin D1.

Current evidence only confirms correlative changes in PI3K/AKT/FKHR phosphorylation after artesunate intervention; there is a lack of target protein binding verification and rescue experiments (eg, PI3K overexpression to reverse artesunate-mediated tumor suppression). Dose-gradient comparative data and cross-subtype in vivo validation across papillary, follicular and anaplastic thyroid carcinoma are absent from existing literature, so causal mechanistic claims should be treated cautiously.

Study on TCM Regulating Immune Microenvironment of Thyroid Cancer

TCM has demonstrated potential anti-tumor effects through modulation of the immune microenvironment in limited preclinical thyroid cancer models. For example, ginsenoside Rg3, an active compound derived from ginseng, exhibits immunomodulatory properties in murine tumor models. Research indicates that ginsenoside Rg3 can remodel the immune microenvironment in subcutaneous thyroid cancer xenografts59 by inhibiting the polarization of tumor-associated macrophages (TAMs), decreasing the secretion of immunosuppressive cytokines such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β), and augmenting the activity of CD8+ T cells. Furthermore, ginsenoside Rg3 suppresses tumor angiogenesis and impedes tumor growth and metastasis by downregulating VEGF expression in vivo.59

Similarly, Astragalus polysaccharide (APS), another bioactive constituent of TCM, exerts anti-thyroid cancer effects by enhancing the host immune response. Empirical studies have demonstrated that APS can increase the activity of NK cells and cytotoxic T lymphocytes (CTLs), stimulating the secretion of cytokines such as interferon-gamma (IFN-γ) and interleukin-2 (IL-2), thereby strengthening the body’s capacity to eliminate tumor cells.58 Additionally, APS contributes to the improvement of the thyroid cancer58 immune microenvironment by inhibiting the proliferation of regulatory T cells (Tregs) and mitigating immunosuppressive mechanisms.

All supporting data come from rodent xenograft studies; human primary thyroid tumor tissue validation, standardized dose-response testing and immune pathway rescue assays are missing, making it impossible to define the precise molecular cascade through which APS modulates anti-tumor immunity.

Intervention of TCM on Metastatic Mechanism of Thyroid Cancer

TCM can impede the metastasis of thyroid cancer through multiple mechanisms. For instance, ginsenoside Rg3 has been demonstrated to diminish the formation of pseudopodia in tumor cells by suppressing the activity of Rho GTPase family proteins, including Rac-1 and Cdc42, thereby inhibiting cellular migration and invasion.59 Furthermore, ginsenoside Rg3 can attenuate extracellular matrix degradation and inhibit tumor invasion and metastasis by downregulating the expression of matrix metalloproteinases, specifically MMP-2 and MMP-9.59

Similarly, curcumin, another bioactive compound derived from TCM, inhibits thyroid cancer metastasis by targeting the EMT process. Empirical evidence indicates that curcumin upregulates E-cadherin expression while downregulating N-cadherin and Vimentin expression, thereby suppressing EMT and reducing tumor cell migration and invasion.59 Additionally, curcumin impedes tumor cell proliferation and metastasis by inhibiting the Wnt/β-catenin signaling pathway.59

EMT and Wnt pathway alterations are merely correlative readouts; no direct target engagement or pathway rescue assays confirm curcumin acts specifically via Wnt/β-catenin to suppress metastasis. Cross-subtype animal validation and human clinical specimen evidence are absent, so mechanistic conclusions are preliminary and non-generalizable.

Clinical Practice of Thyroid Cancer Treated with TCM

Clinical investigations of TCM as monotherapy for thyroid cancer primarily emphasize symptom alleviation, enhancement of patients’ quality of life, and extension of survival duration. For instance, a clinical trial involving patients with thyroid cancer demonstrated that treatment with formulations aimed at soothing the liver, regulating qi, resolving phlegm, and dissipating masses, such as Chaihu Shugan Powder and Haizao Yuhu Decoction, resulted in a 30% reduction in neck mass and a significant improvement in quality of life scores.56 Another study reported that postoperative thyroid cancer patients receiving prescriptions designed to supplement qi and nourish yin, as well as promote blood circulation and remove blood stasis (eg, Bazhen Decoction and Taohong Siwu Decoction), exhibited a marked decrease in serum thyroglobulin (Tg) levels and tumor recurrence rates.60

Furthermore, TCM monotherapy demonstrated a favorable safety profile for the management of thyroid cancer. A retrospective analysis of 500 patients with thyroid cancer revealed an adverse reaction incidence of only 5% associated with TCM treatment, predominantly mild gastrointestinal discomfort and rash, which resolved spontaneously.60 These findings suggest that TCM is well-tolerated and safe for patients with thyroid cancer.

The integration of TCM with radiotherapy and chemotherapy has been shown to enhance the therapeutic efficacy and mitigate treatment-related adverse effects. For example, a randomized controlled trial indicated that the objective response rate among patients with thyroid cancer receiving combined TCM and radioactive iodine therapy was 80%, significantly surpassing the 60% response rate observed with radioactive iodine alone.56 Additionally, combination therapy substantially reduces the common side effects of radiotherapy and chemotherapy, including nausea, vomiting, and fatigue, thereby improving patients’ quality of life.60

Moreover, adjunctive chemotherapy with TCM may increase chemosensitivity. One study demonstrated that the combination of artesunate with cisplatin in thyroid cancer treatment significantly improved the objective response rate to 75% compared to 50% with cisplatin monotherapy.12 Artesunate also potentiates cisplatin-induced apoptosis by inhibiting the PI3K/AKT signaling pathway.12

In the context of postoperative rehabilitation for thyroid cancer, TCM applications focus on symptom relief, promotion of wound healing, and the prevention of recurrence and metastasis. A clinical study reported that patients treated postoperatively with qi-replenishing and spleen-invigorating prescriptions, along with blood circulation-promoting and blood stasis-removing formulations such as Buzhong Yiqi Decoction and Taohong Siwu Decoction, experienced significant reductions in fatigue scores and shortened wound healing times.61 Another study found that acupuncture yielded an 85% efficacy rate in treating dysphagia following thyroid cancer surgery, significantly outperforming the 60% efficacy rate of conventional treatments.61

In addition, TCM has demonstrated potential for reducing postoperative recurrence and metastasis. A retrospective study revealed that the five-year recurrence rate among patients with thyroid cancer receiving TCM post-surgery was 10%, which was significantly lower than that observed in patients who did not receive TCM.60 These findings underscore the valuable role of traditional Chinese medicine in postoperative management and rehabilitation of thyroid cancer.

Limitations and Heterogeneity of Current TCM Clinical Evidence

While multiple observational studies demonstrate tangible clinical benefits of TCM combined with conventional thyroid cancer treatment,56,60 the reliability and generalizability of these positive results are limited by widespread study heterogeneity and fundamental methodological flaws, which are rarely systematically discussed in previous narrative reviews.

First, nearly all existing clinical evidence relies on retrospective single-center cohorts with limited sample volume; large-scale prospective, double-blinded multicenter RCTs with unified syndrome differentiation standards, fixed herbal prescriptions and consistent objective tumor endpoints are still absent.56 Research protocols differ drastically across publications: variable TCM pattern typing standards, inconsistent treatment durations, and overreliance on subjective quality-of-life scores rather than objective markers including thyroglobulin and imaging metastasis status greatly reduce cross-study comparability.56

Second, a subset of long-term follow-up cohorts yields neutral or negative findings that are seldom summarized.60 Several real-world analyses failed to detect statistically significant differences in 5-year recurrence rates between patients receiving combined TCM and standard therapy versus standard therapy alone; subtle endocrine disturbances after long-term herbal intake have also been documented but underdiscussed.60 Overemphasis on favorable single-arm outcomes creates one-sided evidence interpretation.

Third, safety and drug-interaction data remain incomplete.56 Few trials systematically monitor adverse herbal reactions or characterize interactions between herbal compounds, radioactive iodine and targeted agents. Uniform dose–effect standards for compound TCM formulas have not been established, and chronic toxicity risks of prolonged herbal intervention lack systematic verification.56 Collectively, these defects restrict the translation of promising preclinical TCM results into standardized clinical integrative management protocols for thyroid cancer.

Controversies and Future Prospects

The safety and efficacy of TCM in the management of thyroid cancer remain a subject of considerable debate.56 Certain studies have demonstrated that TCM interventions for thyroid cancer exhibit favorable safety profiles and therapeutic benefits, including enhancement in patients’ quality of life and prolonged survival.56,60 Conversely, other investigations have highlighted the limited evidentiary support for TCM in this context, noting the paucity of large-scale, multicenter, randomized controlled trials, prominent cross-study heterogeneity, underreported neutral/negative clinical results, and raising concerns regarding the potential toxicity of some TCM constituents.56

For instance, specific TCM components, such as aconite, possess inherent toxic properties, which may precipitate adverse reactions if administered improperly.56 Furthermore, the criteria employed to assess the efficacy of TCM in thyroid cancer treatment lack standardization; some studies rely predominantly on subjective symptom improvement without incorporating objective tumor markers or imaging data.56 These methodological inconsistencies contribute to the ongoing controversies surrounding the safety and effectiveness of TCM in this clinical domain.

The standardization and personalization of TCM for thyroid cancer treatment face significant challenges. First, there is no universally accepted framework for TCM treatment based on syndrome differentiation, resulting in variability in therapeutic approaches among practitioners for identical patient presentations.56 Second, considerable heterogeneity exists among patients with thyroid cancer in terms of age, sex, pathological subtype, and disease stage, necessitating individualized treatment strategies. However, the scientific foundation for tailoring TCM interventions to these individual patient characteristics remains insufficiently developed.56

Moreover, the mechanistic underpinnings of TCM’s effects in thyroid cancer have not been well elucidated, with a notable lack of molecular-level evidence impeding the establishment of standardized treatment protocols.12,56 Specifically, the active compounds, molecular targets, and signaling pathways involved in TCM-mediated therapeutic effects are yet to be comprehensively characterized, thereby limiting both the standardization and personalization of TCM approaches in this setting.

Future research directions for TCM in thyroid cancer treatment encompass several key areas: (1) conducting large-scale, multicenter, randomized controlled trials to rigorously evaluate the safety and efficacy of TCM interventions while systematically incorporating neutral and negative trial outcomes into evidence synthesis;56 (2) advancing mechanistic studies to clarify the molecular targets and signaling pathways implicated in TCM’s therapeutic actions;12 (3) developing standardized treatment protocols that include unified criteria for syndrome differentiation, therapeutic regimens, and objective efficacy evaluation metrics;56 (4) exploring integrative treatment modalities combining TCM with contemporary medical therapies, such as targeted agents and immunotherapies, within full-cycle thyroid cancer management;62 (5) innovative novel TCM formulations, including nanotechnology-based and sustained-release preparations, to enhance bioavailability.63

Additionally, there is a pressing need to bolster international research collaborations to facilitate the global recognition and application of standardized TCM adjuvant therapy in thyroid cancer management.56 This includes conducting international multicenter clinical trials and cooperative mechanistic and efficacy studies with global partners.56 Concurrently, efforts should be intensified to cultivate expertise in standardized TCM research and reduce reporting bias in clinical outcome summaries.56

In summary, while TCM holds considerable promise as a complementary approach in thyroid cancer therapy supported by preclinical and small observational data, severe limitations including heterogeneous trial design, scarce high-level evidence and underreported negative findings restrict its routine clinical application. Further rigorous, standardized investigation is essential to substantiate its safety and efficacy and to expand evidence-based integrative therapeutic options available to patients afflicted with this malignancy.

Conclusion

The global incidence of thyroid cancer has increased mainly due to overdiagnosis of papillary microcarcinoma, with stable mortality. Driver gene mutations activate oncogenic signaling pathways and form an immunosuppressive microenvironment, promoting tumor progression. Modern multimodal imaging, molecular testing, surgery, radioiodine, targeted and immunotherapy have greatly advanced precise thyroid cancer management. TCM serves as an effective adjuvant therapy. Herbal active compounds inhibit tumor proliferation, metastasis and immune suppression, and combined TCM–western treatment alleviates symptoms, improves quality of life and reduces recurrence. However, TCM research suffers from inconsistent syndrome standards, scarce high-quality multicenter RCTs, underreported negative results and unclear herbal safety data. This review uniquely integrates modern precision oncology and standardized TCM intervention, and objectively evaluates the limitations of existing TCM evidence. Future research needs large prospective clinical trials, in-depth mechanistic studies, unified TCM treatment protocols and international collaborations to validate the clinical value of TCM. In short, TCM shows great potential for whole-cycle thyroid cancer care, but more rigorous evidence is needed to support standardized integrated therapy.

Funding Statement

Training Program for Outstanding Community‑oriented Talents of the Health System in Pudong New Area, Shanghai.

Disclosure

The authors declare that they have no affiliations with or involvement in any organization or entity with any financial interest in the subject matter or materials discussed in this manuscript.

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