Advancement in tumor treating fields of mechanism, clinical applications, and future directions

Abstract

Traditional cancer treatment modalities, such as surgical interventions, radiotherapy, and chemotherapy, persist as the cornerstone of standard care across a wide array of clinical settings. Despite their established effectiveness in combating cancer, these therapies are inherently invasive in nature and have great side effects, which seriously affect the quality of life of patients. Tumor Treating Fields is a low-intensity intermediate-frequency alternating electric field. Based on the current clinical study of Tumor Treating Fields in brain tumors, The U.S. Food and Drug Administration (FDA) initially approved Tumor Treating Fields in 2015 for the treatment of newly diagnosed or relapsed glioblastoma multiforme (GBM) and in 2019 for the treatment of malignant pleural mesothelioma (MPM). However, Tumor Treating Fields is still not widely appreciated in the treatment of high-mortality cancers, and although the therapeutic effect of Tumor Treating Fields has been validated in cell experiments and clinical trials, how to optimize its therapeutic effect remains to be studied. In this paper, the mechanism of Tumor Treating Fields treatment and its clinical progress were reviewed, and the dosimetry and numerical simulation of individualized treatment were comprehensively summarized, in order provide new ideas for further clinical research of this treatment model.

Introduction

In October 2022, the Annual Report to the Nation on the Status of Cancer, which provides statistics on incidence and mortality rates of different types of cancer and highlights the progress and challenges in prevention, early detection, and treatment [1]. Traditional cancer treatment methods include surgery, radiation therapy, and systemic treatment such as targeted therapy, immunotherapy, and chemotherapy [2]. However, relying solely on surgery cannot completely remove malignant tumors in late-stage cancer patients [3, 4]. When undergoing radiotherapy or chemotherapy for cancer, patients bear short-term and long-term toxicities, imposing significant physical, emotional, and economic burdens and seriously affecting their quality of life [5]. Although targeted therapy and immunotherapy have achieved significant efficacy in some solid tumors with relatively low recurrence rates post-treatment, the effectiveness of precision therapeutic drugs in most solid tumor treatments depends on the molecular profiling results of the tumor [6]. Therefore, new therapeutic interventions and combination treatment approaches are needed to improve the overall survival rate of late-stage cancer patients.

Tumor Treating Fields (TTFields) therapy is the fourth anti-cancer treatment method following surgery, radiation therapy, and anti-tumor drugs [7]. As a non-invasive physical method for treating cancer, it operates under an intermediate frequency (100–300 kHz) and low-intensity (1–3 V/cm) alternating electric field, inhibiting mitosis, and reducing the proliferation of malignant cells, thereby reducing tumor growth [8, 9]. Research as early as 2004 have indicated that alternating electric fields in the 100–500 kHz intermediate frequency range have anti-mitotic effects [10]. TTFields have demonstrated clear efficacy with minor side effects primarily limited to the skin. Additionally, it selectively targets cancer cells through multiple mechanisms without affecting healthy cells and tissues [11, 12]. TTFields therapy was approved by the FDA in 2015 for the treatment of newly diagnosed and recurrent glioblastoma (GBM) [13] and in 2019 for the treatment of locally advanced or metastatic malignant pleural mesothelioma (MPM) [14]. Besides this two approved indications TTFields have shown reliable efficacy and tolerable safety in clinical practice on pancreatic, ovarian, lung cancer when used concomitantly with standard therapy [15–18].

Although there is increasing evidence of the application of TTFields in various tumors, researchers still lack a comprehensive theory regarding the mechanism of action of TTFields at the organ scale [19]. Phenomena observed at the cellular or subcellular level may not explain the effects demonstrated in the complex real tumor microenvironment [20]. The oncology community holds conflicting views on the application of TTFields in a wider range of solid tumors [21]. On the other hand integration of the conception of dosimetry in TTFields treatment is required to establish effective framework in terms of power and usage [22]. This article mainly discusses the mechanism of action of TTFields, preclinical research on TTFields, clinical trials of TTFields combined with other treatment methods in high-mortality and high-incidence solid tumors, as well as the progress of dosimetry research in the field of TTFields and the application of numerical models in personalized treatment plans.

The antitumor mechanism of TTFields

Electric fields have been clinically applied in benign neuropathy for many years. Neurostimulator such as deep brain stimulator (DBS) also showed anti-proliferation on tumor cell line [23]. As we know DBS frequency range is hundreds of opposing to hundreds of kilohertz in TTFields, suggesting internalized and external fields both have therapeutic effect in tumor with a wide range of frequency and adjustable intensity [24]. Cancer cells may be susceptible to TTFields as their electrical properties might differ from those of non-cancer cells, especially when exposed to the kHz frequency range [25]. The involved mechanism was firstly focused on anti-mitosis then expanded to more pathophysiologic reaction including tumor cell proliferation, migration, invasion, immune response in tumor microenvironment, DNA damage repair and replication stress, permeability change of cell membrane and blood-brain-barrier, cell autophagy [19, 26, 27]. This article primarily discusses the anti-tumor mechanisms of TTFields in the following six sections (Fig. 1).

Fig. 1.

Potential mechanism of anti-tumor induced by TTFields

TTFields’ anti-mitotic and cell proliferation effects

Compared to normal cells, one of the hallmarks of cancer cells is uncontrolled proliferation and a high division rate [28]. TTFields disrupt key cellular structures involved in mitosis, hindering the correct division of cancer cells in a field strength and frequency depended on manner. This ultimately leads to cell cycle arrest, impaired tumor growth, and slowed disease progression [29].

TTFields inhibit cell division by disrupting spindle microtubules, reducing proliferation, and causing mitotic catastrophe, leading to cancer cell death [30]. They affect cellular physiology by influencing dipoles in proteins like intermediate filaments and microtubules, applying forces that disrupt mitotic spindle assembly and cause mitotic delays [31]. During mitosis, TTFields induce cellular stress and decrease proliferation, typically resulting in mitotic disruption and subsequent cell death in cells exposed to TTFields. In preclinical models of pancreatic cancer, TTFields exhibit anti-proliferative effects on highly aggressive pancreatic cancer cells and reduce the long-term clonogenicity of individual pancreatic cancer cells [32].

TTFields inhibit tumor cell migration and invasion

Studies have shown that TTFields exhibit a profound inhibitory impact on the proliferation, migration, and invasion of tumor cells [33]. At the cellular level, TTFields induce remarkable and highly specific alterations in microtubule organization. These induced changes, in turn, profoundly disrupt the precise directionality and inherent stability of cancer cell migration. Robust research evidence indicates that these modifications in microtubule organization are capable of potently activating the GEF-H1/RhoA/ROCK signaling pathway [34]. This activation subsequently triggers a cascade of cellular events, leading to the formation of focal adhesions and significant structural alterations within the actin cytoskeleton. Moreover, TTFields effectively impede the migration and invasion of tumor cells by exerting a profound influence on cytoskeletal dynamics, which comprehensively encompasses actin, microtubules, intermediate filaments and mesenchymal stromal cells (MSCs) [35]. Through this mechanism, TTFields play a pivotal role in preventing the metastatic dissemination of cancer [36]. The electric field generated by TTFields disrupts the intricate organizational integrity of the cytoskeleton, thereby affecting the protein structures that are crucial for resisting external mechanical forces and maintaining the overall structural integrity of the cell. Notably, the interference with actin filament formation serves as a key factor that significantly restricts the migratory and invasive potential of tumor cells, thus representing a crucial aspect of TTFields’ anti-cancer mechanism [37].

In addition to migration and invasion, angiogenesis is also an important factor in tumor metastasis. TTFields have the effect of inhibiting tumor angiogenesis, capable of reducing the levels of hypoxia-inducible factor 1 alpha (HIF1α) and vascular endothelial growth factor (VEGF) in GBM cells, decreasing the expression of related genes, thereby inhibiting angiogenesis [33]. Moreover, TTFields can also prevent angiogenesis in osteosarcoma endothelial cells by suppressing the expression of matrix metalloproteinase-2(MMP-2) and VEGF, enhancing drug penetration, and affecting tumor progression [38].

Additionally, the inhibition of diffusion, migration, and invasion by TTFields also depends on parameters such as frequency [23, 39, 40], intensity [41, 42], duration [43, 44], direction [12, 34, 45], and cellular volume [44] of TTFields.

TTFields induced anti-tumor immune response

Recent studies suggested that TTFields may enhance downstream anti-tumor immune responses in addition to their direct effects on cancer cells. While the specific mechanisms are still under investigation, the following are some potential ways in which TTFields may impact tumor immune responses:

TTFields induce immunogenic cell death and boost anti-tumor effects when paired with anti-PD-1 therapy. Voloshin et al. [46] found that TTFields can stimulate anti-tumor immunity and synergize with anti-PD-1 in solid tumor mouse models. This was evidenced by increased cancer cell phagocytosis by dendritic cells (DCs) and the attraction of mature DCs and immune cells, resulting in improved tumor control.

TTFields boost immune cell infiltration, as shown in a 2009 study by Kirson et al. [47] in VX-2 tumor rabbit models. Lung metastases in treated rabbits had deeper mononuclear cell infiltration than controls. Treated rabbits also had higher counts of CD4, CD8, and CD45 T cells, with CD4 cells predominating in tumors. This suggests TTFields’ potential to inhibit primary tumor metastasis and activate anti-tumor immune responses post-treatment.

TTFields stimulate the immune system via micronuclei clusters that activate cGAS and AIM2, enhancing pro-inflammatory and interferon responses in tumors [48]. Chen et al. showed that TTFields activate the immune system by increasing pro-inflammatory and interferon cytokines in tumor cells via cGAS/STING and AIM2 pathways, inhibiting tumor growth and enhancing anti-tumor immunity, indicating a potential immunomodulatory role in GBM [49]. Single-cell sequencing reveals that TTFields upregulate immune checkpoints like death-ligand-1(PD-L1), protein-4(CTLA-4), and TIGIT on tumor cells, activating the adaptive immune system and enhancing cytotoxic T lymphocyte and CD8 + T cell infiltration in tumors [50].

TTFields inhibit DNA damage repair and induce replication stress

TTFields have been verified to enhance the efficacy of drugs that induce DNA damage and replication stress. TTFields can potently inhibit the DNA repair mechanism in cancer cells, thereby augmenting the effects of DNA-damaging agents [51]. Additionally, TTFields elicit replication stress by downregulating the expression of genes that are pivotal for mitosis and replication [52]. TTFields have been shown to significantly downregulate BRCA and Fanconi anemia (FA) pathway genes. After radiation treatment, TTFields cause a marked slowdown in DNA repair rate. Within 48 h, the number of residual (unrepaired) DNA lesions increases substantially. This likely contributes to TTFields-induced cell death, these genes are crucial for DNA damage and repair [42]. Exposure to electric fields by TTFields boosts DNA double-strand break repair foci, increasing R-loop formation and causing DNA damage and cell death. It also decreases MCM10 and MCM6 gene expression, slowing replication fork speed, which are vital for DNA replication [53]. By inhibiting these pathways, TTFields can weaken the ability of cancer cells to activate DNA damage repair mechanisms.

TTFields alter the permeability of cell membranes and the blood–brain barrier (BBB)

TTFields can alter the cell membrane structure, significantly enhancing the membrane’s permeability to chemotherapeutic drugs. After exposure to TTFields, cell bioluminescence is enhanced, the binding and entry of membrane-related reagents (such as Dextran – FITC, Ethidium D) increase and scanning electron microscopy shows a significant increase in the number and size of pores on the cell membrane. All these directly demonstrate the improvement of cell membrane permeability. In-depth research indicates that after the alternating electric field stops, the enhanced bioluminescence and increased number of membrane pores caused by TTFields exposure disappear within 24 h, suggesting the reversibility of this phenomenon. Additionally, based on the mechanism of TTFields, evidence shows that compounds like 5-aminolaevulinic acid (5-ALA) can enhance membrane accessibility. These compounds are expected to be used to improve the penetration of diagnostic and therapeutic drugs into cancer cells, opening up new avenues for cancer diagnosis and treatment [54]. Additionally, TTFields reversibly penetrate the BBB. The function of the BBB is collectively coordinated by endothelial cells [55]. Increased permeability of the blood-brain barrier allows drugs to be directly delivered to the brain, aiding in the treatment of central nervous system tumor diseases. However, one of the biggest challenges currently is the difficulty in crossing the barrier to deliver drugs to the central nervous system [56]. The research has confirmed that TTFields have the potential to facilitate drug penetration across the BBB. E. Both in vivo and in vitro evaluations of the effects of TTFields on GBM have been conducted [57, 58]. The research indicates that TTFields reversibly alter the integrity and permeability of the BBB at a frequency of 100 kHz, and the barrier remains open when switching from 100 kHz to 200 kHz TTFields frequency [58].

TTFields induce autophagy

Autophagy is a physiological cellular process that plays a dual role in cancer progression, exerting either promotional, inhibitory, or transformative effects on tumors [59]. TTFields trigger autophagy in cancer cells by causing mitotic abnormalities and ER stress, enhancing resistance to therapy [60]. In the research conducted by Silginer et al. [41], it was discovered that when cells were exposed to TTFields or CCCP (carbonyl cyanide m-chlorophenyl hydrazone, a prototype inducer of canonical caspase-dependent apoptosis), the levels of LC3A/B-II, a crucial biomarker for autophagy, exhibited a discernible increase. Employing transmission electron microscopy (TEM) for in-depth examination, the cells exposed to TTFields manifested typical characteristics associated with autophagy. In stark contrast, the cells treated with CCCP displayed distinct and characteristic changes indicative of apoptosis. Subsequently, the researchers cultured glioma cells using the autophagy inhibitor 3-methyladenine. The experimental results demonstrated that upon blocking the autophagic process, the number of dead cells resulting from TTFields exposure was significantly reduced. This finding strongly suggests that autophagy plays a pivotal role in mediating TTFields-induced cell death. Experimental results from in vitro and in vivo models of colorectal cancer (CRC) demonstrate that the combination of TTFields and 5-FU can induce autophagy in colon cancer cells, increase cell death, and exhibit potential anti-tumor effects [61]. The activation of autophagy can enhance the anti-GBM activity of TTFields in both in-vitro and in-vivo experiments, as well as in the stem cells of GBM patients or primary in-vivo culture systems. Research findings have revealed that TTFields treatment can upregulate multiple autophagy-related genes and trigger cellular morphological changes. Through the mTOR/p70S6K signaling pathway, the autophagy process induced by TTFields in GBM is associated with a decrease in the expression level of Akt2 [62]. This research achievement has clearly identified autophagy as a key cell death pathway triggered by TTFields in GBM, and meanwhile indicates that TTFields hold promise as a potentially effective treatment option for GBM. Furthermore, a substantial amount of pre-clinical evidence indicating the involvement of autophagy in cancer cell survival has spurred an increase in clinical trials. Currently, numerous clinical trials are underway, aiming to evaluate the therapeutic potential of combining autophagy inhibitors with chemotherapy.

Preclinical research of combined therapy in TTFields treatment

Enhancing progression-free and overall survival in cancer patients is a critical challenge, prompting research into more effective treatment strategies. Studies have been conducted on various cancer models, including GBM, MPM, Ovarian, and Lung cancer, to assess safety and efficacy of combined therapies. Details of experiments conducted on tumor cell lines are provided in Table 1.

Table 1.

Effects of TTFields combined with drugs on various tumor cells

Cancer type	Cell	Drug	Concentration/dose	TTFields parameters	Time and effect	References
Glioma	U-118	DTIC	0.001–100 mM	200 kHz, 1.75 V/cm	72 h, Proliferation ↓ DTIC(IC50: 6.4 mM) DTIC-TTFields(IC50: 0.023 mM)	[69]
	U87-MG, KNS42, SF188	Paclitaxel Mebendazole	High vs. low concentration	130 kHz, 10.0 V/cm, 450 µS	Cell viability↓, Synergistic effect	[23]
GBM	U373, U87	Sorafenib	0–20 µM	150 kHz, 0.9–1.5 V/cm	48 h, cell viability, migration, invasion, angiogenesis ↓	[111]
	Patient-derived GBM Stem-like cells (GSCs)	TMZ	300 µM	200 kHz, 1 V/cm	8 d, Proliferation ↓, Antitumor effect ↑	[70]
	U251-MG (U251), MZ-54 (17)	Dex	65 µM	200 kHz, 1.48 V/cm-1.41 V/cm	72 h, PFS, OS no change	[39]
MPM	MSTO-211 H, NCI-H2052	Cisplatin pemetrexed	1–10,000 nM 1-100 nM	150 kHz, 1 V/cm	72 h, Pemetrexed + TTFields: Apoptosis↑ C&P + TTFields: proliferation and clonal formation ↓	[42]
Ovarian cancer	A2780, OVCAR3 Caov-3	Paclitaxel	0-100nM	200 kHZ 2.7 V/cm	72 h, A2780 (CI 1.03), OVCAR3 (CI 0.81), Caov-3 (CI 0.86)	[73]
NSCLC	H157, H4006, A549, H1229	Cisplatin	PCI25(µM): H157:1, H4006:0.75, A549:2, H1229:2	100–200 kHz	24 h/48 h/72 h, CI > 1	[52]
	H157, H1229	Olaparib IR	Olaparib 10µM IR: 1 Gy/2Gy	100–200 kHz	24 h/48 h/72 h, Olaparib + IR + TTFields: CI > 1 Olaparib + IR/Olaparib + TTFields: CI ≈ 1	[52]
	H1229, HTB-182, LLC1, KLN205	Pemetrexed Cisplatin Paclitaxel	0–0.1 nM 0–10 nM 0–100 nM	150 kHz, 1.75 V/cm	72 h, Proliferation ↓, colonies ↓	[112]
	HCC827	Erlotinib	0-20 nM	150 kHz, 1.75 V/cm	72 h, Proliferation ↓, colonies ↓	[112]
Colonic cancer	HCT116 SW480	5-FU	5–20 µmol/L	0.9 V/cm 1.2 V/cm 1.5 V/cm	48 h, Chemical sensitivity↑ Proliferation, migration, invasion↓ Apoptosis, autophagy, Organoid cell death↑	[61]
Cervical cancer	HeLa	Doxorubicin	0–10 μm	120 kHz, 1 Vpp	72 h, Proliferation↓ Chemical sensitivity↑	[78]
Liver cancer	Huh7	Doxorubicin	0–10 μm	120 kHz, 1 Vpp	72 h, Proliferation↓ Chemical sensitivity↑	[78]
Pancreatic cancer	AsPC-1 PC-1.0 (hamster)	Gemcitabine	0–100 nM	150 kHz	72 h, Therapeutic effect↑	[82]
		Irinotecan	0–100 nM
		5FU	0–1000 μm
		Paclitaxel	0–100 nM
Breast cancer	BT-474, JIMT-1	Trastuzumab	5 µg/ml	0.9 V/m	72 h, Proliferation ↓	[80]
	EmtR1 MCF-7/Mx MDA-MB-231/Dox	Doxorubicin	0.001–100 µM	150 kHz 1.75 V/cm	72 h, Chemical sensitivity↑	[81]
		Paclitaxel	0.0001–100 µM
	MDA-MB-231	Doxorubicin	0–10 µM	150 kHz	72 h, Proliferation ↓, Doxorubicin vs. Doxorubicin-TTField(IC50: 0.04µM vs.0.002µM) Paclitaxel vs. Paclitaxel-TTFields (IC50: 5.00nM vs.0.005nM) Cyclophosphamide vs. Cyclophosphamide-TTFields (IC50: 6.60mM vs.0.004mM)	[69]
		Paclitaxel	0–1000 nM	1.75 V/cm
		Cyclophosphamide	0–100 mM

DTIC dacarbazines, IC₅₀ half maximal inhibitory concentration, CI combination index, h, hour, d day; ↑ up-regulate; ↓ down-regulate, GBM glioblastoma, TMZ temozolomide, Dex dexamethasone, OS overall survival, PFS progression-free survival, MPM malignant pleural mesothelioma, C&P Cisplatin and pemetrexed, NSCLC non-small cell lung cancer, IR interventional radiology, 5-FU 5-fluorouracil

In vitro studies: mechanistic synergies

GBM

TTFields after exposure play a key role in DNA DSB repair via the FA gene, slowing DNA repair post-radiation and leading to cell death through mitosis mechanisms [52, 63]. Giladi et al. [64, 65] carried out a study in which the efficacy of applying Tumor Treating Fields (TTFields) following radiotherapy (RT) or penicillin-induced DNA damage was thoroughly tested in U-118 MG and LN-18 glioma cells. Moreover, the combination of TTFields with proton therapy not only increases apoptosis but also effectively inhibits the migration of glioblastoma (GBM) cells. It also synergistically inhibits cancer cell growth and enhances apoptosis in NSCLC [53, 66] and pancreatic cancer cell lines [43]. The combination of RT and TTFields shows potential for other tumor types, with research focusing on DNA damage and repair mechanisms.

TTFields combined with chemo drugs like paclitaxel, temozolomide, and sorafenib show additive effects, significantly increasing drug sensitivity. The combination treatment with sorafenib notably inhibits tumor cell migration, invasion, and angiogenesis, further enhancing TTFields’ therapeutic efficacy [67]. Branter et al.’s [68] study shows that combining TTFields with paclitaxel and Temozolomide(TMZ), in both low and high doses, decreases tumor cell line activity more than single treatments, especially in pediatric brain tumor cell lines. This combination enhances chemotherapy drug sensitivity and improves TTFields’ therapeutic efficacy by inhibiting tumor cell migration, invasion, and angiogenesis [69]. TTFields with TMZ show synergistic anti-tumor effects, inhibiting tumor cell proliferation [70]. Linder [39]et al.found dexamethasone limits radiation therapy efficacy but not the cell death induced by TTFields in glioma.When combined with the CUSP9v3 drug, Tumor Treating Fields (TTFields) synergistically inhibit glioblastoma through multiple mechanisms: not only impairing the non-directional motility of tumor cells, but also significantly enhancing apoptosis by inducing decreased mitochondrial outer membrane permeability (MOMP), increased cleavage of effector caspase 3, and downregulated expression of anti-apoptotic proteins Bcl-2 and Mcl-1. Concurrently, this combination elicits metabolic reprogramming in vitro, collectively mediating synergistic antitumor activity [71].

MPM

The study by Mumblats.H [42] et al. demonstrates that the combination of TTFields with cisplatin or pemetrexed, as well as three-drug combinations, enhances the therapeutic effect on mesothelioma cells in vitro, revealing the synergistic interaction of TTFields with drug combination therapy. Additionally, the efficacy of TTFields in mesothelioma cell lines is also dependent on various parameters such as application frequency, intensity, and duration of treatment.

Ovarian cancer

TTFields and paclitaxel both utilize microtubules as a targeting mechanism. TTFields disrupt microtubule proteins and inhibit the microtubule polymerization process promoted by paclitaxel, thus interfering with the stable microtubule structure, and producing a synergistic effect [72]. When TTFields are combined with chemotherapy drugs such as paclitaxel, they exhibit a synergistic effect, helping to overcome drug resistance. Research indicates that in human ovarian cell cultures, the inhibitory effect of the combination therapy is significantly greater than that of using chemotherapy drugs alone, indicating that TTFields enhance the efficacy and sensitivity of chemotherapy [73]. Additionally, studies have shown that TTFields in combination with carboplatin or PARP inhibitors (PARPi) synergistically induce homologous recombination repair deficiency (HRD) in ovarian cancer cells. By enhancing disruption of the DNA damage repair pathway, this combination significantly reduces tumor cell resistance to chemotherapy and targeted therapies [74].

Lung cancer

The study conducted by Karanam [53] et al. utilized four human non-small cell lung cancer (NSCLC) cell lines (H157, H4005, A549, and H1229), and initiated concurrent treatment with TTFields, cisplatin, and other platinum-based chemotherapy drugs. The research found that TTFields synergistically enhanced the efficacy of cisplatin in NSCLC cell lines, increasing their sensitivity. Additionally, when TTFields were used in combination with Olaparib alone, they exhibited synergistic cytotoxic effects, and the addition of IR to the treatment regimen further enhanced cytotoxicity. In the study by Giladi.M [75] et al., combining TTFields with chemotherapy drugs such as pemetrexed, cisplatin, and paclitaxel significantly inhibited the proliferation and clonal formation of NSCLC cells, suggesting that adding TTFields to chemotherapy regimens could enhance the therapeutic effects of cell lines, potentially providing a feasible approach to improving clinical outcomes.

Other tumours

Colorectal cancer (CRC) holds the distinction of being the most prevalent cancer type and is associated with a high mortality rate [76]. Lee [61] et al. confirmed in a colon cancer model that, compared to monotherapy, the combination treatment of TTFields and 5-FU significantly inhibits tumor cell proliferation, migration, and invasion. Additionally, TTFields combined with sorafenib can effectively inhibit colorectal tumor growth by inhibiting the AKT/STAT3 signaling pathway [77]. This suggests that CRC patients may benefit from combination therapy in clinical trials. In cervical cancer and hepatocellular carcinoma studies, the combination application of TTFields with the anticancer drug Doxorubicin on HeLa and Huh7 cell lines showed that TTFields significantly inhibited cancer cell proliferation and enhanced cancer cell sensitivity to chemotherapy drugs [78, 79]. This indicates a synergistic effect between the two, providing a new treatment strategy with minimal side effects. In breast cancer tumor cell lines, the combination of TTFields with Trastuzumab effectively inhibited cell proliferation and increased the sensitivity of HER2-positive human breast cancer cells to Trastuzumab [80]. Additionally, TTFields, either alone or in combination with paclitaxel and doxorubicin, significantly reduced the viability of both wild-type and multidrug-resistant (MDR) cell subpopulations, indicating its potential efficacy in treating drug-resistant tumors [81].

In vivo studies: translational validation

TTFields enhance the efficacy of medications, demonstrating synergistic anti-tumor effects in animal models by inhibiting tumor growth and reducing both tumor volume and weight. This combinatorial approach also extends survival rates, underscoring its potential to improve clinical outcomes.

To assess skin tolerability of radiation energy delivered through TTFields sensor arrays, a rat model was utilized, with daily 2 Gy irradiation (cumulative dose: 20 Gy) administered via ceramic sensor arrays. The results showed no induction of adverse skin reactions, including edema, inflammation, hemorrhage, or fibrosis [64]. Concurrently, the study confirmed that TTFields in combination with radiation therapy (RT) significantly enhances anti-tumor activity against glioblastoma cells. When paired with proton therapy, TTFields not only improve treatment sensitivity and inhibit glioblastoma growth in vivo without common side effects but also suppress the tumor’s in vivo progression [65]. In vitro evaluations of TTFields on pancreatic cancer cells revealed its ability to inhibit tumor cell proliferation and reduce long-term clonogenic potential. Synergistic enhancements in therapeutic efficacy were observed when TTFields were combined with chemotherapy agents such as gemcitabine, irinotecan, 5-fluorouracil (5FU), or paclitaxel, further validating its translational potential for abdominal malignancies [82]. Wei Lin [83]et al. tested the efficacy of TTFields combined with anti-PD-1/PD-L1 immunotherapies in non-small cell lung cancer (NSCLC) mouse models, demonstrating that this combination enhances anti-PD treatment response by inducing immunogenic cell death. This mechanism upregulates the expression of chemokines CCL2/8 and CXCL9/CXCL10 in NSCLC models, thereby fostering a pro-immunogenic tumor microenvironment conducive to enhanced immune checkpoint blockade efficacy.

Preclinical research has focused on cancers such as glioblastoma (GBM), ovarian, liver, pancreatic, and lung malignancies. For detailed preclinical data on TTFields combined with pharmacological therapies, refer to Table 2.

Table 2.

Effects of combination therapy in animal models

Cancer type	Animal models	Drug	Concentration	TTFields parameters	Time and effect	References
GBM	BALB/c nude mice (inoculated with U373 cells)	Sorafenib	30 mg/kg	150 kHz, 1 V/cm	7 d, Tumor weight ↓ Tumor volume↓ TTFields sensitivity ↑	[111]
MPM	Rat in situ model IL-45 and mouse subcutaneous model RN5	Cisplatin Pemetrexed	Situ model: Cisplatin (1 mg/kg), pemetrexed 5 mg/kg, subcutaneous model: Cisplatin (4 mg/kg) Pemetrexed (100 mg/kg)	150 kHz, 1.2 V/cm	7 d, Treatment alone compared tumor volume↓	[42]
HCC	Male SD rats (inoculated with N1-S1 cells)	Sorafenib	10 mg/kg/day	150 kHz, 2.4 V/cm	5 d, ≥ 18 h/d Sorafenib-TTFields vs. Sorafenib/TTFields: Tumor volume and weight↓	[113]
Ovarian cancer	Female C57BL/6 mice (MOSE-LTICv cells)	Paclitaxel	20 mg/kg	200 kHz, 2 V/cm	7 d, Tumor volume and weight↓	[73]
NSCLC	C57BL/6 mice (inoculated with LLC1 cells), DBA/2 mice (5 × 104 KLN205-T1 cells)	Pemetrexed	1 mg/kg, 5 mg/kg	150 kHz, 1.86 ± 0.67 V/cm	6 d, Tumor volume↓	[112]
		Cisplatin	20 mg/kg twice a day
		Paclitaxel	Every 3 days
	Male C57BL/6 mice (inoculated with LCC-2 cells)	anti-PD-L1	250 µg	–	7 d, tumor volume↓ CD45  tumor infiltrating cell↑	[50]
Pulmonary metastasis	Female C57BL/6 mice (inoculated with B16F10 melanoma cell line)	–	–	100 kHz, 1.8–2 V/cm	7 d, The size and number of melanoma metastases↓ , average lung weight↓	[47]
	Adult New Zealand white rabbits (implanted with VX-2 tumor fragments)	–	–	200 kHz, 2.6 ± 0.3 V/cm	35 d, The size and number of melanoma metastases↓ mOS ↑ (70 d vs.57 d)	[47]
Colonic cancer	Nude mice (injected with HCT116 cell line)	5-FU	30 mg/kg	1 V/cm	7 d, Tumor volume↓ Tumor weight ↓, normal tissue showed no pathological abnormality	[61]
Pancreatic cancer	Male Syrian Golden Hamsters (implanted with PC-1.0 tumor)	Gemcitabine, 5-FU	2.5 mg/kg 45 mg/kg	150 kHz, 1.6 ± 0.1 V/cm	7 d, Tumor volume↓ Tumor weight ↓	[82]
Breast cancer	Male BALB/c nude mice (inoculated with BT-474 cells)	Trastuzumab	150 µg	0.9 V/m	5 d, Sensitivity ↑ , Tumor volume↓	[80]

GBM glioblastoma, d day, ↑ up-regulate, ↓ down-regulate, MPM malignant pleural mesothelioma, HCC hepatocellular carcinoma, NSCLC non-small cell lung cancer, anti-PD-L1 anti-programmed death-ligand 1, mOS median overall survival, 5-FU 5-fluorouracil

Clinical efficacy of TTFields in combination therapy for malignant tumors

Clinical trials

Clinical trials have evaluated TTFields’ safety and efficacy in treating GBM and various extracranial tumors, including mesothelioma, NSCLC, pancreatic, ovarian, liver, and gastric cancers. These trials have shown TTFields to inhibit tumor growth in different types of cancer and extend survival. Ongoing studies are further exploring the application of TTFields. For specific trial data, refer to Table 3, and for details on active trials, see Table 4; Fig. 2.

Table 3.

Completed clinical trials of tumor treating fields

Study name	Study identifier	Phase	Research population	N	Treatments	Clinical results
EF-11	NCT00379470	III	rGBM	237	TTFields vs. chemotherapy	OS: 6.6 vs. 6.0 mo AEs: 6% vs. 16%
EF-14	NCT00916409	III	ndGBM	695	TMZ + TTFields vs. TMZ	OS: 11.8 vs. 9.2 mo PFS: 6.7 vs. 4.0 mo
–	NCT01894061	II	rGBM	25	Bevacizumab + TTFields	OS: 10.5 mo; PFS: 4 mo
–	NCT03477110	I	ndGBM	30	TMZ + Scalp-Sparing Radiation + TTFields	mOS: 15.8 mo mPFS: 9.3 mo
STELLAR	NCT02397928	II	MPM	80	Pemetrexed + platinum+ TTFields	mOS: 18.2 mo mPFS: 7.6 mo
PANOVA	NCT01971281	II	PDAC	40	Gemcitabine + TTFields vs. gemcitabine + nab- paclitaxel + TTFields	mOS: 14.9 mo vs. not reached yet mPFS: 8.3 mo vs.12.7 mo
EF-15	NCT00749346	II	NSCLC (IIIB–IV)	41	Pemetrexed + TTFields	mOS: 13.8 mo
LUNAR	NCT02973789	III	NSCLC	276	ICI or DTX + TTFields vs. ICI or DTX alone	mOS: 13.2 mo vs. 9.9 mo
INNOVATE	NCT02244502	II	Ovarian cancer	31	Paclitaxel + TTFields	mOS: not reached yet OSR (1-year): 61% mPFS: 8.9 mo
HEPANOVA	NCT03606590	II	HCC	27	Sorafenib + TTFields	ORR: 18%; DCR: 91% AEs: no safety concerns
EF-31	NCT04281576	II	GEJC/GC	28	TTFields + XELOX	mOS: 12.2 mo; mPFS: 7.8 mo; ORR: 50%
	NCT01755624	II	Brain metastases	18		Time to local and distant progression in the brain

rGBM recurrent GBM, GBM glioblastoma, TTFields tumor treating fields, OS overall survival, mo month, AEs adverse events, ndGBM newly diagnosed GBM, TMZ temozolomide, PFS progression-free survival, mOS median overall survival, mPFS median progression-free survival, MPM malignant pleural mesothelioma, PDAC pancreatic ductal adenocarcinoma, NSCLC non-small cell lung cancer, ICI immune checkpoint inhibitor, DTX docetaxel, OSR overall survival rate, HCC hepatocellular carcinoma, ORR objective response rate, DCR disease control rate, GEGC gastroesophageal junction cancer, GC gastric cancer, XELOX capecitabine/oxaliplatin

Table 4.

Summary of selected ongoing clinical trials of tumor treating fields

Study identifier	Phase	Status	Research population	N	Treatments	Primary objective(s)
NCT05310448	Not applicable	Recruitment	Brainstem gliomas	10	TTFields	Incidence of adverse events
NCT04471844	3	Active, not recruitment	ndGBM	950	RT + TMZ + TTFields vs. RT + TMZ	OS
NCT03377491	3	Active, not recruitment	PDAC	556	TTFields + Gemcitabine + Nab-paclitaxel	OS
NCT04605913	2	Recruitment	PDAC	40	mGCN + TTFields	Determine safety of mGCN + TTFields
NCT05679674	2	Recruitment	PDAC	48	SABR + TTFields	mPFS
NCT04892472	2	Recruitment	Advanced or Metastatic NSCLC	100	TTFields(150 kHz)+pembrolizumab	ORR
NCT05341349	1	Recruitment	BM(melanoma)	10	TTFields + SRS + ICI	Incidence of grade 3 CNS toxicity
NCT03940196	3	Active, not recruitment	Recurrent Ovarian Cancer	540	TTFields + Weekly Paclitaxel	OS
NCT03203525	1	Recruitment	Advanced, Recurrent, or Refractory Hepatic Metastatic Cancer	52	TTFields + Chemotherapy + Bevacizumab	MTD
NCT05004025	1	Recruitment	Metastatic Uveal Melanoma	10	TTFields + Nivolumab + Ipilimumab	ORR
NCT05092373	1	Recruitment	Advanced Solid Tumors Involving the Abdomen or Thorax	36	TTFields + Cabozantinib/ Pembrolizumab + Nab-Paclitaxel	MTD
NCT05746325	Not applicable	Recruitment	Leptomeningeal Metastases of the Spine (Breast Cancer)	5	TTFields	Incidence of significant toxicity

TTFields tumor treating fields; ndGBM newly diagnosed GBM, GBM glioblastoma, RT radiotherapy, TMZ temozolomide, OS overall survival, PDAC pancreatic ductal adenocarcinoma, mGCN modified nab-paclitaxel, cisplatin and gemcitabine, SABR stereotactic ablative body radiation, mPFS median progression-free survival, NSCLC non-small cell lung cancer, ORR objective response rate, BM brain metastasis, SRS stereotactic radiosurgery, ICI immune checkpoint inhibitor, CNS central nervous system, MTD maximum

Fig. 2.

TTFields clinical trials in multiple tumors

GBM

Glioblastoma (GBM) is the most common primary brain tumor, and patients have a very poor prognosis and low survival rates [84]. The current standard of care involves maximal surgical resection and chemoradiotherapy with TMZ [85], but the highly infiltrative nature of GBM hinders complete surgical resection [86].

The pilot clinical trial EF-07 in 2004 treated 10 rGBM patients with TTFields for 280 weeks, showing a median OS of 62.2 weeks, over double that of historical controls, with no serious adverse events related to single therapy, suggesting TTFields’ safety and efficacy [87]. In the phase III EF-11 trial for rGBM, 237 patients were enrolled, with 120 receiving TTFields monotherapy and 117 chemotherapies alone. TTFields monotherapy (median survival 6.6 months) was comparable to the Best Physician’s Choice group (median survival 6.0 months), but with lower systemic toxicity and improved quality of life (QoL). High compliance (≥ 75%, i.e., at least 18 h per day) with TTFields resulted in a median OS of 7.7 months, while compliance under 75% yielded a median OS of 4.5 months [88].

Preclinical studies suggest that combining TTFields with chemotherapy enhances therapeutic effects [69, 81]. Preclinical studies suggest that combining TTFields with chemotherapy enhances therapeutic effects. The EF-14 trial involved 695 patients with newly diagnosed glioblastoma (ndGBM), comparing TTFields + TMZ to TMZ alone. The combination therapy significantly improved PFS and OS, with median OS reaching 19.6 months (intent-to-treat) and 20.5 months (per-protocol) for the combination versus 16.6 and 15.5 months for TMZ alone. The mPFS was 7.1 months for TTFields + TMZ versus 4.0 months for TMZ alone [89, 90]. Additionally, a prospective study (EF-29) in Japanese patients with newly diagnosed glioblastoma (ndGBM) further validated the real-world safety and efficacy of TTFields therapy: no new safety signals were identified, and 70% of the 40 enrolled patients reported skin-related adverse events (AEs), primarily manifesting as dermatitis, pruritus, and eczema—local skin injuries consistent with previous clinical data, without severe or unexpected toxic reactions [91].

An open-label phase II (NCT01894061) study combining TTFields with Bevacizumab in rGBM showed a median PFS of 4.1 months and OS of 10.5 months, indicating the safety and effectiveness of TTFields in combination therapies without impacting QoL or increasing severe adverse events [92]. A pilot study (NCT03477110) [93] assessed TTFields combined with scalp-sparing chemoradiation in 30 ndGBM patients, with a median age of 58. Treatment included scalp-sparing radiation (60 Gy in 30 fractions), TMZ (75 mg/m²), and TTFields (200 kHz). The primary endpoint was skin toxicity-related discontinuation within 30 days post-treatment; secondary endpoints were median PFS and OS. The study reported a median PFS of 9.3 months and OS of 15.8 months, with no TTFields-related toxicities, indicating safety and feasibility for future treatments. Ongoing trials are further evaluating TTFields’ safety and efficacy in this patient group.

Clinical trial in MPM

TTFields have demonstrated efficacy in cancers beyond GBM, including MPM. The Phase II trial STELLAR (NCT02397928) treated 80 unresectable MPM patients [14], with TTFields plus standard chemotherapy (pemetrexed and cisplatin or carboplatin). The primary endpoint was overall survival (OS), with a median follow-up of 12.5 months (IQR: 7.4–16.6), a median OS of 18.2 months (95% CI 12.1–25.8), and a median PFS of 7.6 months (95% CI 6.7–8.6), better than historical control data. No increase in systemic toxicity was seen, confirming TTFields’ safety in MPM treatment. In addition, a feasibility study evaluating TTFields in combination with pemetrexed and platinum-based chemotherapy for unresectable malignant pleural mesothelioma reported that all patients experienced Grade 1–2 skin irritation within the TTFields sensor array region [94]. Notably, no patients encountered Grade 3 or higher device-related toxicity. These findings are highly consistent with prior safety data and further substantiate the tolerability of TTFields combination therapy.

Clinical trial in PDAC

The Phase 2 PANOVA trial (NCT01971281) studied 40 newly diagnosed PDAC patients, evaluating TTFields with gemcitabine, and with gemcitabine plus nab-paclitaxel [15]. The primary endpoint was safety, with PFS and OS as secondary endpoints. The TTFields and gemcitabine group showed a median PFS of 8.3 months and OS of 14.9 months. The addition of nab-paclitaxel extended median PFS to 12.7 months. Historically, these rates were higher with TTFields, and the combination was safe and well-tolerated.

The Phase III PANOVA-3 trial (NCT03377491) is underway to confirm these effects in advanced metastatic pancreatic cancer, focusing on OS as the primary endpoint. Additionally, PANOVA-3 trial (NCT04605913) is assessing the safety of combining TTFields with gemcitabine, nab-paclitaxel, and cisplatin in metastatic pancreatic cancer patients. Additionally, a Phase II trial (NCT05679674) is exploring the potential of chemotherapy and stereotactic ablative body radiotherapy (SABR) in combination with TTFields to slow tumor growth in locally advanced pancreatic cancer, aiming to evaluate their synergistic effects.

Clinical trial in NSCLC

A single-arm phase I/II clinical trial (NCT00749346) [95] investigated TTFields with pemetrexed in 41 advanced NSCLC patients, showing the combination was safer and more effective than pemetrexed alone, with a median OS of 13.8 months and a one-year survival rate of 57%. There were no serious TTFields-related adverse events, only mild to moderate contact dermatitis.

The phase III LUNAR trial (NCT02973789) [96] further investigated the efficacy of TTFields (150 kHz) in 276 metastatic NSCLC patients, comparing TTFields plus standard of care (SOC), which included docetaxel (DTX) or immune checkpoint inhibitors (ICIs), to SOC alone. The trial showed a significant increase in median OS with TTFields added to SOC (13.2 vs. 9.9 months, HR: 0.74, P = 0.035). In the subgroup receiving ICI and TTFields, median OS was 18.5 months vs. 10.8 months for ICI alone (HR: 0.63, P = 0.030). For DTX, the median OS was 11.1 months with TTFields vs. 8.7 months for DTX alone (HR: 0.63, P = 0.28). These results indicate that TTFields combined with SOC significantly improve OS compared to SOC alone, particularly with ICI therapy.

Additionally, the pilot study Keynote B36 (NCT04892472) is evaluating the safety and effectiveness of TTFields plus pembrolizumab in first-line treatment of NSCLC, with the primary endpoint being objective response rate (ORR), and secondary endpoints including OS, PFS, and safety [97]. The research results are eagerly anticipated, and it is hoped that they can provide strong evidence to support clinical practice.

Clinical trial in brain metastases

Brain metastases may lead to a series of serious health problems and complications, significantly impacting the patient’s quality of life and overall health. Timely diagnosis and treatment are necessary to alleviate symptoms and improve survival quality. The COMET trial (NCT01755624) will recruit 60 patients with 1–5 cases of non-small cell lung cancer brain metastases. So far, 17 patients have participated in the trial, with 6 patients in the TTFields group and 11 patients in the control group. The trial aims to evaluate the effectiveness and safety of TTFields treatment in systemically controlled non-small cell lung cancer patients. Trial results show that, so far, no TTFields-related serious adverse events (SAE) have been observed, demonstrating the safety and tolerability of TTFields in NSCLC brain metastases patients [98]. Furthermore, the METIS trial (NCT02831959) is testing the safety and neurocognitive outcomes of TTFields in 1–10 brain metastases (BM) from non-small cell lung cancer. In this trial, 270 patients will be randomly assigned to receive either stereotactic radiosurgery (SRS) or a combination of TTFields and SRS. The primary endpoint is the time to brain progression based on the RANO-BM criteria or neurologic death [99].

Clinical trial in ovarian cancer

The Phase 2 single-arm clinical trial INNOVATE (NCT02244502) evaluated the safety and effectiveness of TTFields (200 kHz) in combination with weekly paclitaxel for patients with recurrent ovarian cancer(PROC), including 31 patients with recurrent, platinum-resistant, unresectable ovarian cancer [18]. The primary endpoint was safety, and secondary endpoints included overall survival (OS), progression-free survival (PFS), and response rate (RR). The clinical trial results indicated that it was safe for platinum-resistant recurrent ovarian cancer. The median PFS was 8.9 months (95% CI 4.7–NA), with 7 patients (25%) showing partial responses and a clinical benefit rate of 71%. The median OS was not reached, with a one-year survival rate of 61%, and no serious adverse events related to TTFields were reported. Furthermore, the Phase III trial, INNOVATE-3 (NCT03940196), will further test the effectiveness of TTFields in combination with weekly paclitaxel for the treatment of recurrent ovarian cancer patients.

Clinical trial in HCC

Advanced hepatocellular carcinoma (HCC) is a primary liver cancer associated with poor prognosis [100]. The Phase II HEPANOVA study (NCT03606590) tested TTFields combined with sorafenib in 27 patients with advanced HCC [95]. Patients received TTFields (150 kHz) for at least 18 h a day along with sorafenib (400 mg twice daily). The primary endpoint was overall response rate (ORR), and the study found an ORR of 9.5% and a disease control rate (DCR) of 76%, with a median PFS of 5.8 months, higher than sorafenib monotherapy. In patients completing 12 weeks of treatment, the ORR was 18% and DCR was 91%. TTFields extended survival without increasing AEs, with 70% experiencing skin-related AEs. An ongoing trial (NCT03203525) is investigating TTFields with chemotherapy and bevacizumab for advanced liver metastasis, evaluating AE incidence and ORR.

Clinical trial in other tumors

A phase II trial (NCT04281576) is assessing TTFields with XELOX in 28 patients with unresectable advanced GEJC or GC, showing a higher ORR (50% vs. 45%) and a mOS of 12.2 months with no TTFields-related adverse events [101]. Uveal melanoma is the most common ocular malignancy for adults and despite effective therapies, roughly 50% of patients will develop metastatic disease, leading to a poor prognosis. A single-arm trial (NCT05004025) is recruiting for metastatic uveal melanoma, combining TTFields with Nivolumab and Ipilimumab, with ORR as the primary endpoint. Another trial (NCT05092373) is recruiting for advanced abdominal or chest tumors to test TTFields with cabozantinib, nab-paclitaxel, and atezolizumab, with primary endpoint MTD and secondary endpoints ORR, PFS, and OS.

Cost-effectiveness analysis

Cost-effectiveness analyses from the perspectives of the U.S. and Chinese healthcare systems (Table 5) reveal divergent economic profiles for TTFields combination therapies in newly diagnosed glioblastoma (nGBM) and metastatic non-small cell lung cancer (mNSCLC).

Table 5.

TTFields cost-effectiveness results for the US and China

Country	Study name	Research population	Treatments	Incremental cost	Life years	QALYs	ICER/QALY	References
USA	EF-14	nGBM	TTFields + TMZ vs. TMZ	$188,637	1.25	0.96	$197,336	[114]
China	EF-14	nGBM	TTFields + TMZ vs. TMZ	$ 57,849	–	2.46	$23,474	[115]
USA	LUNAR	mNSCLC	TTFields + ICI/Docetaxel	$59,663	0.92	0.66	$89,808	[116]
			TTFields + ICI	$70,901	1.67	1.21	$58,764
			TTFields + Docetaxel	$50,505	0.23	0.17	$306,029
China	LUNAR	mNSCLC	TTFields + ICI/Docetaxel	$74,688	0.67	0.26	$284,490	[117]
			TTFields + ICI	$78,115	1.15	0.42	$187,434
			TTFields + Docetaxel	$71,307	0.25	0.13	$546,386

nGBM newly diagnosed glioblastoma, mNSCLC metastatic non-small cell lung cancer, QALYs quality-adjusted life-years, ICER incremental cost-effectiveness ratio

In the U.S. healthcare context, the incremental cost-effectiveness ratio (ICER) of TTFields combined with temozolomide (TMZ) for nGBM falls within the country’s willingness-to-pay threshold, establishing its cost-effectiveness. However, analysis in the Chinese context shows that the ICER of this combination significantly exceeds the defined willingness-to-pay standard, classifying it as not cost-effective. For metastatic NSCLC, in the U.S., TTFields therapy—when combined with either immune checkpoint inhibitors (ICI) or docetaxel—extends mean overall survival and improves quality-adjusted life years (QALYs), with ICERs below local cost-effectiveness thresholds, demonstrating clear economic advantages. In contrast, while TTFields plus ICI or docetaxel yields substantial health benefits in China, the incremental costs far surpass the country’s medical affordability: patients, families, and the public healthcare system face heavy economic burdens, with treatment-related expenses vastly exceeding the value of health benefits. As a result, no subgroup protocol passed the cost-effectiveness evaluation.

The aforementioned differences highlight the substantial disparities among various medical systems in terms of payment capacity, health resource allocation strategies, and cost-benefit evaluation criteria. Therefore, it is essential to develop an individualized plan tailored to regional economic characteristics for clinical application.

Dosimetry and computer modelling in clinical research

Cell and clinical studies shed light on TTFields’ mechanism and efficacy but face limitations like long durations, high costs, and restricted solid tumor applications. The electric field distribution of TTFields is also affected by organ geometry, electrode placement, and tissue properties [102]. The electrical conductivity and dielectric constants of different human tissues (such as skin, fat, muscle, bone, and diseased organs) are usually different, and the properties of diseased tissues often differ from those of normal tissues [103, 104]. Therefore, a thorough understanding of the dosimetry of TTFields in tumor distribution and how to optimize the delivery of TTFields is crucial. In recent years, with the continuous advancement of computer technology, specific software can be used to calculate the distribution of field intensity, and numerical modeling methods are commonly employed to calculate the electric field distribution within human organs and tumors.

The EF-14 trial is the foundational experiment for establishing the concept of TTFields therapy, involving 340 brain tumor patients receiving TTFields treatment and conducting finite element simulations of TTFields delivery [105]. The study suggests that the dose of TTFields can be defined based on power and usage, delivering higher doses of TTFields to the tumor bed can improve overall survival (OS). Simulations of TTFields administration and related analyses of overall survival demonstrate a linear quadratic relationship between dose and effect [106]. Therefore, like radiation therapy, the principle of TTFields planning is to maximize the average dose in the intervention area.

In practical use, there is a trend towards reducing the dose compared to the prescribed dose. It is crucial to maximize regional density while minimizing wear and tear. Determining the dose of TTFields is an essential step before applying it to the chest or abdomen, and different scales of modeling are being conducted to gain a deeper understanding of the relationship between clinical outcomes and TTFields parameters [22].

The individualized computer models of patients in the LUNAR III clinical trial show heterogeneity in electric field penetration affecting the total tumor volume (GTV) by up to 200% [107]. Such results highlight the use of simulation methods and algorithms in individualized planning for optimal solutions and continuous monitoring. The strength of TTFields is calculated using the fractional anisotropy finite element (FE) method, maximizing field strength in the tumor by more effectively placing arrays [108]. The FE method has been successfully applied to determine the optimal TTFields intensity at the head drilling position in brain tumor patients [109]. However, these techniques may underestimate anatomical changes caused by disease in real patients (such as edema, midline shift, etc.). Emerging research utilizing mathematical models to predict tumor progression presents a promising attempt to incorporate TTFields dose distribution [110]. In future studies, computational models should not only achieve the required precision in the distribution of electrical properties among different tissues but also establish more options for short-term wear patterns of TTFields in personalized planning. When developing treatment plans, precise modeling of tumor tissue characteristics may be necessary to accurately simulate the electric field distribution near the tumor, maximizing the efficacy of this exciting therapeutic approach, ultimately leading to improved patient outcomes.

Conclusion

TTFields’ innovative model of intervening in tumor cell division through low-frequency alternating electric fields has shown therapeutic potential for various solid tumors in both basic research and clinical translation. TTFields can significantly inhibit tumor cell proliferation in vitro and delay the growth of solid tumors in vivo by inhibiting mitosis and inducing apoptosis, whether used as a single modality or in combination with chemoradiotherapy. In clinical applications, TTFields have improved overall survival rates, demonstrating their safety and efficacy.Numerical simulation technology based on finite element analysis optimizes field strength, frequency, and the heterogeneous electrical properties of tumors and local tissues via computer simulations, providing quantitative support for individualized program design. This approach overcomes the limitations of traditional experimental conditions and offers references for subsequent biological and clinical experiments.

However, the widespread application of TTFields is still constrained by several practical challenges. Treatment requires patients to wear the device for more than 18 h per day, which may lead to irritant dermatitis due to prolonged skin contact with the sensor array. Additionally, the weight of the device and the visibility of body surface patches can impose dual burdens on daily activities and social psychology, reducing compliance in some patients. Furthermore, the issue of uneven electric field distribution in complex anatomical sites (e.g., thoracoabdominal surfaces) remains unresolved, and the limited adaptability of existing patches may compromise treatment efficacy. From a health economics perspective, the high cost of equipment far exceeds the affordability of medical insurance in most regions, posing a significant bottleneck to clinical adoption.

In the future, integrating lightweight device design, novel electrode materials, and geometric optimization of patches to accommodate complex anatomical structures with personalized dose simulations could facilitate the development of precision treatment strategies. Such advancements would not only enhance cost control but also open new avenues for improving the prognosis of patients with refractory tumors.

Author contributions

Meiqi Zang: Writing—original draft preparation, writing—review and editing. Song Zhu: Writing—review & editing. Qiang Niu: Writing—review and editing.

Funding

Not applicable.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.