Cancer: A bioelectric disease?
In order to progress beyond descriptive observations, a quantitative, systems‐level synthesis of membrane potential across cancer models is required. Although individual studies have demonstrated V m alterations in specific systems, a comparative framework integrating these findings across tumour types, measurement techniques and functional outcomes is lacking. 56
In this section, we integrate experimental evidence from model organisms, cell lines and patient‐derived systems to identify common V m patterns and their functional consequences. This approach enables us to identify conserved bioelectric features of malignancy and provides a foundation for quantitative comparisons and translational applications.
Cancer cells consistently exhibit depolarised membrane potentials across diverse experimental systems, compared to their non‐transformed counterparts. 34 This shift is observed across species, tumour types and measurement platforms, indicating that depolarisation is a conserved bioelectric hallmark of malignancy. In order to establish membrane potential as a measurable and comparable parameter across tumour systems, a quantitative synthesis is performed. Table 1 summarises the ranges of V m reported, the experimental models used and the associated phenotypic states across cancer types. It provides a quantitative overview of V m values across representative cancer models, including measurement approaches and associated functional outcomes.
The comparison reveals that cancer cells typically occupy a depolarised membrane potential range of approximately −10 to −50 mV. In contrast, differentiated or non‐proliferative cells are more commonly found in hyperpolarised states ranging from −50 to −90 mV. It is important to note that these values are not static; V m exhibits dynamic fluctuations depending on cell‐cycle phase, metabolic state and microenvironmental context. However, direct quantitative comparisons between studies are limited by methodological differences, such as the use of patch‐clamp electrophysiology versus optical voltage imaging, and variations in calibration protocols.
Despite methodological variability the directionality of V m changes is highly consistent. This suggests that depolarisation is not merely a model‐specific observation, but reflects a generalisable bioelectric feature of malignant transformation. 6 , 12
These findings support the interpretation of V m as a quantitative state variable that captures functional differences between malignant and non‐malignant cells. Similar conclusions have also been reached in breast cancer models in which experimental alteration of the bioelectric state was sufficient to suppress malignant behaviour, further supporting V m as a functional parameter, not merely a descriptive correlate. 12 , 59 , 60 This provides a measurable and potentially actionable biomarker across cancer systems.
Although depolarisation is a common feature across many tumour systems, the regulation of membrane potential and the mechanisms by which it is established vary substantially between tumour types, molecular subtypes, and microenvironmental contexts, as do its functional consequences. This heterogeneity is evident in that solid tumours, such as those of the breast, brain and stomach, often exhibit pronounced depolarisation driven by coordinated ion‐channel remodelling. In contrast, haematological malignancies tend to rely more strongly on intracellular signalling and metabolic coupling, resulting in less well‐defined V m signatures. 3 , 5 , 23 , 24 , 47
In addition, tumour stage and differentiation state influence bioelectric profiles. Early‐stage tumours and proliferative cell populations tend to occupy dynamic V m regimes associated with cell‐cycle progression. In contrast, advanced or therapy‐resistant tumours often stabilise depolarised states linked to stemness and plasticity. 5 , 15 These differences suggest that V m should not be interpreted as a uniform marker, but as a context‐dependent parameter reflecting tumour heterogeneity.
Therefore, a systematic mapping of V m distributions across tumour entities, molecular subtypes and disease stages is essential for translating bioelectric concepts into precision oncology. This would facilitate the identification of tumour‐specific bioelectric signatures and enhance patient stratification for V m‐targeted interventions.
A central and consistently observed feature across cancer systems is the close relationship between membrane potential and proliferative capacity. V m acts as a dynamic regulator of cell‐cycle progression and not merely as a passive correlate of cellular activity, with specific voltage states being associated with particular transitions in the cell cycle. 20 , 22 , 23 , 58
Proliferative cells occupy a depolarised V m regime across multiple models, typically ranging from approximately −10 to −50 mV, whereas quiescent or differentiated cells exhibit more hyperpolarised states. Importantly, however, this relationship is not monotonic, but phase‐specific. Cell‐cycle progression is accompanied by reproducible V m oscillations: hyperpolarisation is required for DNA synthesis during the S phase, while depolarisation facilitates transitions into the G1 phase and mitosis. 20 , 21 , 22 , 25 These findings suggest that V m acts as a gating variable for cell‐cycle checkpoints, not merely indicating proliferation. 20 , 21 , 22 , 25
These voltage‐dependent effects mechanistically emerge from coordinated changes in ion‐channel activity and membrane organisation. Depolarisation has been shown to rearrange charged phospholipids within the plasma membrane, promoting the clustering of signalling molecules such as K‐Ras and activating downstream MAPK pathways. 36 This establishes a direct link between membrane biophysics and canonical oncogenic signalling. Conversely, enforced hyperpolarisation, achieved through the pharmacological or genetic manipulation of ion conductances, induces reversible cell‐cycle arrest by inhibiting DNA synthesis and mitotic entry. 10 , 12
Further experimental perturbation studies demonstrate that the magnitude and timing of V m changes are both critical. Moderate depolarisation is necessary for proliferation to begin, whereas excessive or prolonged depolarisation can disrupt the continuity of the cell cycle and induce arrest or cytotoxicity. For instance, blocking potassium channels with 4‐aminopyridine induces depolarisation and G1 arrest in multiple myeloma cells. Combining this with chemotherapeutic agents such as paclitaxel enhances the antiproliferative effects by disrupting phase‐specific V m coordination. 58 , 62 These observations suggest that cancer cells rely on precisely regulated V m trajectories, not fixed voltage states. 25 , 48 , 58 , 62
The tissue context may further influence these trajectories. In breast cancer, for example, left–right asymmetries in incidence and aggressiveness have been linked to corresponding epigenetic and bioelectric differences. These include altered methylation of hyperpolarising ion channel genes, as well as side‐dependent effects on membrane depolarisation and Ca2 + influx. 63 , 64 , 65 , 66 These findings suggest that the regional patterning of bioelectric control of proliferation may also exist at the tissue level.
In addition to ion‐channel‐mediated effects, membrane potential is closely linked to metabolic regulation. Activation of AMP‐activated protein kinase (AMPK) in gastric cancer cells induces membrane hyperpolarisation via modulation of chloride transport, resulting in S‐phase arrest and reduced proliferation. 17 , 29 , 47 This coupling of energy status, ion transport and V m provides further support for the interpretation of membrane potential as an integrative regulator that coordinates metabolic and proliferative decision‐making.
The membrane potential is also closely linked to metabolic regulation, forming an integrated bioelectric–metabolic network that supports tumour growth and adaptation. The activity of transporters involved in nutrient uptake, including glucose and amino acid transporters, is directly influenced by ion gradients maintained by V m. 17 , 26 , 29 , 36 , 67 Conversely, metabolic pathways regulate ion channel activity and pump function, thereby shaping the bioelectric state.
Experimental evidence shows that metabolic sensors, such as AMP‐activated protein kinase (AMPK), can modulate V m by regulating ion transport. This leads to hyperpolarisation and cell‐cycle arrest in gastric cancer cells. 47 , 68 Conversely, depolarised states are often associated with increased glycolytic activity and metabolic reprogramming, which supports proliferation and survival. Emerging studies further indicate that ion‐channel activity and V m dynamics are tightly coupled to key metabolic pathways, including glycolysis and oxidative phosphorylation, linking bioelectric regulation to cellular energy homeostasis and redox balance. 17 , 23 , 29 , 36 , 69
This bidirectional coupling suggests that V m not only regulates cellular behaviour, but also reflects metabolic state. 67 , 69 Therefore, integrating bioelectric measurements with metabolic profiling could provide a more comprehensive understanding of tumour physiology and identify new vulnerabilities for therapeutic intervention. These findings establish V m as a phase‐specific control parameter of cell‐cycle progression. Cancer cells exploit depolarised bioelectric states to sustain proliferation, yet they remain vulnerable to disturbances that disrupt the timing, amplitude or coordination of voltage transitions. This reveals bioelectric control points that can be targeted to selectively interfere with tumour growth. 22 , 23 , 50 , 70
Beyond its role in controlling the cell cycle, membrane potential is a key regulator of transitions in cell state, particularly the balance between stemness and differentiation. This is of critical relevance in cancer, where the persistence of cancer stem cell (CSC)‐like populations is a key driver of tumour progression, therapy resistance, and relapse. 14 , 71
Across multiple systems, CSCs consistently exhibit more depolarised membrane potentials than their non‐malignant or differentiated counterparts. For instance, CSCs derived from human liver tissue exhibit V m values of around −7 mV, whereas normal stem cells display values of approximately −23 mV. 14 , 57 , 71 This depolarised bioelectric state is closely associated with the maintenance of stemness, including the sustained expression of transcription factors such as OCT4, SOX2 and NANOG, and enhanced self‐renewal capacity. 14 , 50 , 71
Experimental manipulation of V m demonstrates a causal relationship between bioelectric state and differentiation potential. Forced hyperpolarisation, achieved through pharmacological, genetic or ionic interventions, promotes differentiation and reduces stem cell‐like properties in multiple cancer models. Conversely, depolarisation suppresses lineage commitment and stabilises undifferentiated states. Notably, even transient depolarisation during the early stages of differentiation can irreversibly inhibit lineage commitment, indicating that V m acts at critical decision points in cell fate determination. 14 , 50 , 55 , 70 , 71
Mechanistically, V m‐dependent control of stemness is mediated through multiple interconnected pathways. Changes in membrane potential regulate calcium influx and intracellular Ca2 + microdomains, influencing transcriptional regulators and epigenetic programmes that govern cell identity. 23 , 29 , 72 In parallel, V m modulates intracellular pH and metabolic fluxes via electrogenic transporters, thereby linking the bioelectric state to metabolic reprogramming. This concept is also consistent with the tumour‐suppressive role of transporters such as SLC5A8, which couple ion gradients to uptake of anti‐proliferative metabolites and thereby connect bioelectric state regulation with epigenetic control. 72 These coupled processes establish V m as an upstream regulator of cell‐state stability, not merely a consequence of differentiation.
Importantly, V m defines a continuum of bioelectric states, not a binary switch. 1 , 17 , 31 , 73 CSCs occupy a depolarised regime that favours plasticity and adaptability, whereas hyperpolarised states promote differentiation, quiescence and reduced tumourigenic potential. This continuum model provides a framework for understanding how cancer cells transition between proliferative, stem cell‐like and differentiated states in response to internal and external stimuli.
In glioblastoma, for example, depolarised CSC‐like cells remain in a quiescent yet therapy‐resistant state, which is partly maintained by voltage‐gated sodium channel activity. 5 Inhibiting these channels pharmacologically induces hyperpolarisation, promotes differentiation and reduces self‐renewal capacity. Channel‐dependent effects related to proliferation and Ca2 + handling have also been described in Ewing sarcoma. Aberrant KCNN1/SK1 expression contributes to the bioelectric control of malignant behaviour in this condition. 74 This demonstrates that bioelectric modulation can reprogram malignant cell states without directly targeting oncogenic mutations.
In addition to the plasma membrane potential, the mitochondrial membrane potential (ΔΨm) is a key bioenergetic parameter that controls ATP production, reactive oxygen species (ROS) generation, and susceptibility to apoptosis. There is increasing evidence of functional coupling between V m, calcium signalling and ΔΨm in cancer cells. Membrane depolarisation can enhance the influx of Ca2 + into the cytosol, which in turn influences the uptake of calcium into the mitochondria and the stability of the ΔΨm, thereby linking the electrophysiology of the plasma membrane to metabolic reprogramming and cell survival pathways. 29 , 47 , 69 Conversely, mitochondrial dysfunction and altered ΔΨm can affect ion channel activity and the cellular redox state, thereby shaping the global bioelectric profile. These findings suggest that bioelectric regulation in cancer involves interconnected membrane systems that integrate plasma membrane voltage with mitochondrial function and metabolic state and establish the membrane potential as a key regulator of cellular plasticity in cancer. By stabilising depolarised bioelectric states, tumours maintain stem cell‐like, therapy‐resistant populations. Conversely, targeted hyperpolarisation is a potential strategy for inducing differentiation, reducing plasticity and increasing therapeutic vulnerability. 17 , 29 , 36 , 47 , 50
In addition to its roles in proliferation and controlling the state of cells, the membrane potential is a key regulator of the migration of cancer cells and the dissemination of metastases. A growing body of evidence indicates that depolarised bioelectric states are associated with increased motility, invasiveness and organ‐specific colonisation across multiple tumour types.
Quantitatively, highly metastatic cancer cells typically exhibit depolarised V m values in the range of approximately −37 to −55 mV. This regime overlaps with proliferative states, but is functionally distinct in its association with migratory behaviour. 15 This suggests that V m does not encode a single phenotype, but instead defines a multidimensional state space in which specific voltage regimes support distinct malignant functions. 15 , 44 , 55 , 74 , 75
Mechanistically, V m influences migration through several interconnected processes. One key pathway involves voltage‐gated sodium channels, which are frequently overexpressed in invasive cancers. Sodium influx through channels such as Nav1.5 and Nav1.7 contributes directly to membrane depolarisation and promotes cytoskeletal remodelling, extracellular matrix degradation and directional migration. 42 , 44 , 45 These effects are partly mediated through coupling to intracellular pH regulation and protease activity, thereby linking bioelectric signals to the biochemical machinery of invasion.
In parallel, V m modulates calcium dynamics, which play a central role in regulating the reorganisation of the actin cytoskeleton, the turnover of focal adhesions, and cell contractility. Depolarisation enhances calcium influx, activating downstream signalling pathways that facilitate migration and invasion. 23 , 29 , 44 , 45 Chloride channels also contribute to this process by regulating cell volume and osmotic balance, which are essential for movement through confined extracellular spaces. These ion fluxes form a coordinated bioelectric–mechanical system that enables metastatic behaviour.
Importantly, emerging evidence suggests that cancer cells can exploit spatial gradients in membrane potential to guide their migration in a specific direction. Bioelectric fields within tissues may provide instructive cues that influence cell movement, in a manner analogous to electrotaxis observed in developmental and wound‐healing contexts. 15 , 31 , 73 , 76 This raises the possibility that tumours utilise endogenous bioelectric landscapes to coordinate invasion and dissemination at the tissue level.