Fig. 3: Summary of the mechanisms of action of TTFields.

Low-intensity, intermediate-frequency, alternating electrical fields exert biophysical forces on a variety of charged and polarisable molecules to elicit a spectrum of biological effects. A Antimitotic effects: during metaphase, the electric fields are uniform, causing dipolar molecules, such as tubulin, to align with the field. TTFields therefore interfere with tubulin polymerisation and depolymerisation during metaphase. At anaphase, TTFields prevent localisation of septin proteins to the mitotic spindle and inhibit assembly of the septin complex into a ring structure at the cleavage furrow. During cytokinesis, the electric fields are non-uniform, with the fields converging on the cleavage furrow, where the field intensity is the highest. As a result, strong dielectric force is applied on polarisable objects, pushing them towards the high-intensity region. Together, these effects result in abnormal chromosome segregation and/or cell death. B DNA repair. TTFields have been shown to downregulate BRCA and Fanconi anaemia (FA) pathway genes, which have been associated with increased replication stress and increased double-strand break (DSB) formation. Additionally, homologous recombination repair (HRR) is impaired by TTFields, resulting in reduced efficiency of DSB repair. C Autophagy. TTFields have been suggested to prevent the inhibitory effects of the PI3K/Akt/mTORC1 signalling pathway on autophagy, resulting in increased activation of autophagy with TTFields therapy. Further studies are needed to ascertain whether autophagy is activated as a cell survival or cell death signal in response to TTFields. D Antitumour immunity. TTFields stimulates macrophages (Mø) to secrete reactive oxygen species (ROS), nitric oxide (NO) and proinflammatory cytokines such as interleukin (IL)-1β, tumour necrosis factor (TNF)-α and IL-6. Additionally, TTFields promote immunogenic cell death via dendritic cell (DC) recruitment and maturation (mat), ultimately leading to an increase in the accumulation of CD4 + and CD8 + T cells at the tumour site. The combination of TTFields with anti-PD-1 therapy might enhance PD-L1 expression in infiltrating DCs and macrophages to further enhance antitumour immunity. E Anti-migratory. TTFields reduce the capacity of cancer cells for migration and invasion through nuclear factor (NF)-κB-, mitogen-activated protein kinase (MAPK)- and phosphatidylinositol 3-kinase (PI3K)/Akt-dependent mechanisms. F Cell membrane permeability. TTFields increase cell membrane permeability by increasing the number and size of holes in the cell membrane, thereby potentially enhancing sensitivity to chemotherapeutic drugs.