Cancer: A bioelectric disease?

Cancer progression is driven by coordinated alterations in signalling networks that regulate proliferation, plasticity, metabolism and therapeutic response. Although genetic and epigenetic mechanisms are well characterised, there is an increasing body of evidence that suggests bioelectric signalling constitutes an additional integrative regulatory layer in tumour biology. In diverse experimental systems, malignant cells consistently exhibit depolarised transmembrane potentials (V m), which correlate with proliferation, stemness, invasion and therapy resistance, suggesting depolarisation as a conserved bioelectric hallmark of malignancy. This shifts the central question from whether cancer can be considered a bioelectric disease to the extent to which bioelectric signalling constitutes a relevant organising dimension of tumour biology.

However, a quantitative, translationally actionable framework for membrane potential in cancer is lacking. Existing studies and reviews have largely focused on individual ion channels, specific tumour contexts, or conceptual aspects of bioelectricity without systematically establishing V m as a cross‐tumour, systems‐level state variable.

Here, we summarise approximately 15 years of experimental and translational research to evaluate the extent to which V m functions as an integrative regulatory dimension of malignancy. Here, we define a state variable as a measurable, dynamically tuneable parameter that integrates multiple regulatory inputs and predicts system‐level cellular behaviour.

At the same time, we identify key limitations in the current evidence base, including limited quantitative comparability across tumour types, incomplete mechanistic integration across regulatory layers, insufficient resolution of tumour heterogeneity and a lack of standardisation for clinical translation.

Based on this review, we introduce a quantitative framework and a structured translational roadmap for incorporating bioelectric state control into precision oncology. This establishes membrane potential as not only a supplementary biomarker, but also a functional pharmacodynamic indicator and an actionable control variable for state‐guided therapeutic intervention.

Keywords: bioelectric biomarkers, bioelectric signalling, cancer bioelectricity, ion channels in cancer, membrane potential (V m), precision oncology, tumour progression and stemness, tumour‐treating fields

The transmembrane potential (V m), also referred to as steady‐state membrane voltage, is generated by asymmetric ionic gradients and selective membrane conductance. Although it was initially studied in excitable tissues, V m is now recognised as a ubiquitous bioelectric state variable that influences and coordinates fundamental cellular processes, such as proliferation, differentiation, migration, and long‐range cell‐to‐cell communication, in non‐excitable tissues. 1 , 2 , 3 In cancer, accumulating evidence suggests that bioelectric dysregulation acts as both a downstream consequence of oncogenic signalling and, in certain contexts, an upstream regulator of malignant behaviour. 2 , 3 , 4 , 5

Cancer cells frequently exhibit depolarised membrane potentials relative to matched non‐transformed cells across tumour types. 6 , 7 , 8 , 9 , 10 , 11 Experimental manipulation of V m can alter proliferation, invasion, differentiation, and phenotypic stability. In selected systems, it can also partially decouple malignant behaviour from specific genetic backgrounds. 3 , 4 , 10 , 12 , 13 , 14 , 15 , 16 These observations suggest that V m extends beyond a descriptive correlate of transformation and represents a reversible, drug‐modulable control variable with diagnostic and therapeutic relevance. 13 , 17 , 18

The idea that bioelectric properties influence proliferation and oncogenic transformation is not new. Early work by H. S. Burr proposed that endogenous bioelectric fields are associated with cancer development, suggesting that alterations in electrical properties may precede morphological changes. This concept was later refined by studies demonstrating that sustained depolarisation accompanies mitotic entry and malignant transformation, whereas hyperpolarisation is associated with growth arrest and differentiation. 19 , 20 , 21 Advances in electrophysiology, calibrated voltage imaging and computational modelling now allow us to more precisely investigate whether V m functions as an upstream regulator, a permissive state variable or a downstream readout of oncogenic processes. 2 , 22 , 23 , 24 , 25 Therefore, an important question is not whether cancer can be considered a bioelectric disease, but to what extent bioelectric signalling constitutes an organising dimension of tumour biology. Addressing this requires expanding channel‐centric perspectives towards a quantitative, systems‐level understanding of membrane potential as an integrative state variable.

Despite this progress, three key gaps remain. Firstly, quantitative comparisons of resting membrane potentials across tumour types are limited. Secondly, most studies focus on individual ion channels or specific tumour contexts, while V m as an integrated, systems‐level variable remains insufficiently addressed. Thirdly, the translational potential of bioelectric state control has not yet been systematically incorporated into precision oncology frameworks. This review addresses these gaps by combining a quantitative synthesis of V m across cancer systems with a mechanistic, systems‐level framework and a structured, translational roadmap.

The membrane potential is a fundamental biophysical property that is required for cellular homeostasis, transport processes, and signalling. Many electrogenic transport mechanisms exploit the membrane potential directly as a source of free energy, thereby linking ionic gradients to nutrient uptake and metabolic regulation. 26 At steady state, V m can be approximated by the Goldman–Hodgkin–Katz equation, which reflects the relative permeabilities and concentrations of major ions. 27 However, in proliferative and malignant cells, V m is inherently dynamic and cannot be fully captured by equilibrium descriptions.

Importantly, V m is not determined by a single ionic species, but emerges from the integrated activity of ion channels, transporters, and electrogenic pumps. While potassium conductances often dominate in differentiated, non‐proliferative cells, sodium, calcium and chloride fluxes, together with transporters such as the Na+/K+‐ATPase and sodium‐coupled nutrient transporters, substantially contribute to V m regulation in proliferative and cancer‐associated states. 23 , 28 , 29 , 30 V m should therefore be understood as an emergent, systems‐level property integrating membrane biophysics with signalling, metabolism, and cell‐state regulation. 1 , 31 , 32 , 33 , 34

Proliferative capacity is closely associated with membrane potential across tissues. Non‐proliferative cells typically exhibit hyperpolarised values of V m, whereas actively dividing and malignant cells operate in more depolarised regimes. 3 , 7 , 8 , 9 , 10 , 20 , 23 , 28 , 30 , 35 However, this distinction is not static, but is instead dynamically regulated during the cell cycle. Quiescent cells are generally hyperpolarised; depolarisation accompanies entry into the G1 phase; hyperpolarisation supports DNA synthesis in the S phase; and further depolarisation occurs during the G2/M transition. 20 , 22 , 25

These voltage transitions are not merely correlative. 20 , 22 Membrane depolarisation can reorganise charged phospholipids, thereby facilitating K‐Ras nanoclustering and the activation of MAPK signalling pathways. 36 Conversely, experimentally induced hyperpolarisation can arrest proliferation reversibly by blocking DNA synthesis and mitotic entry. 10 , 13 These findings support a model in which V m functions as a gating variable for cell‐cycle progression. 34

Over the past decade, a variety of voltage‐to‐biochemistry transduction mechanisms have been identified, including voltage‐dependent regulation of lipid organisation, ion flux‐mediated second messenger signalling (e.g. Ca2 + and pH) and electrostatic control of membrane‐associated signalling complexes. These mechanisms collectively link V m changes to downstream cellular behaviours. 23 , 29 , 36

At a mechanistic level, these states arise from coordinated changes in ion‐channel activity, transporter flux, and pump–leak balance. Non‐proliferative cells are characterised by dominant potassium conductances and robust Na+/K+‐ATPase activity, which maintain hyperpolarised states. 22 , 28 , 37 In contrast, proliferative and malignant cells exhibit increased Na+ influx, altered Ca2 + and Cl− fluxes, and engagement of electrogenic transporters, thereby stabilising depolarised V m states. 13 , 23 , 24 This ensemble‐based remodelling links membrane potential directly to proliferation control.

The membrane potential and ion transport are tightly coupled. V m emerges from the integrated activity of ion channels, transporters and pumps, while simultaneously being regulated by them through the transmembrane electric field. 28 In cancer, this coupling is systematically altered through the coordinated remodelling of ion transport systems, which is often referred to as ‘oncochannelopathies’. 23 , 24 , 38

Voltage‐gated sodium channels, including Nav1.5 and Nav1.7, are frequently overexpressed in multiple cancers, contributing to depolarisation, migration and invasion. 39 , 40 , 41 , 42 , 43 , 44 , 45 Potassium channels such as Kv1.3, Kv1.5 and Kv11.1 (hERG) modulate resting V m and influence proliferation and apoptosis in a context‐dependent manner. 22 , 46 Calcium and chloride channels extend these effects into intracellular signalling networks by linking V m to Ca2 +‐dependent pathways, cytoskeletal dynamics, and volume regulation. 23 , 29 , 33 , 47 , 48 , 49

Importantly, these effects cannot be understood at the level of individual channels alone. Cancer‐associated depolarisation arises from coordinated, network‐level changes in ion transport that integrate electrical, biochemical and mechanical processes. V m therefore represents a systems‐level state variable that links ion‐channel activity with signalling, metabolism, and transitions in cell state (Figure 1). 23 , 24 , 45

This review summarises around 15 years of research into the membrane potential in cancer, with the objective of establishing the regulation of the bioelectric state as an integrative and clinically actionable dimension of malignancy. Focusing beyond individual ion channels or specific tumour entities, we adopt a systems‐level approach, considering V m as a state variable that connects membrane biophysics to signalling networks, metabolic regulation, and cell fate control. 13 , 50

To address current gaps, this review is organised into two complementary parts. The first part provides a quantitative and mechanistic synthesis of V m across tumour systems, integrating evidence from model organisms, cell lines, and patient‐derived samples. The second part translates these insights into a structured roadmap for clinical implementation, including standardised V m measurement, pharmacodynamic validation, and integration into precision oncology frameworks.

Our literature search adhered to the PRISMA 2020 guidelines and included English‐language studies published since 2010 examining membrane potential dynamics or V m‐targeted interventions in cancer models. Of the 358 records screened, 26 met the predefined inclusion criteria. These studies consistently associate depolarised V m states with proliferation, stemness, therapy resistance, and invasive behaviour. This supports the central role of bioelectric state regulation in malignancy.

This review goes beyond descriptive accounts of cancer bioelectricity, integrating mechanistic evidence with translational considerations to inform experimental design, biomarker development, and therapeutic strategies. Crucially, it offers a unified framework combining: (i) a quantitative synthesis of V m across tumours; (ii) systems‐level mechanistic integration of signalling, metabolism and cell‐state regulation; and (iii) a structured roadmap for clinical translation. By explicitly linking these three areas, the study elevates V m from a descriptive parameter to a testable and actionable state variable in precision oncology.

Over the past decade, an increasing number of reviews have emphasised the significance of bioelectric signals and ion channel dysregulation in cancer biology. Pioneering research has laid the groundwork for the concept of oncochannelopathies, which describes how the altered expression and function of ion channels can contribute to the processes of proliferation, migration and metastasis. Comprehensive reviews by Prevarskaya et al. and Litan and Langhans, in particular, have systematically linked potassium, sodium, calcium and chloride channels to key hallmarks of cancer, including uncontrolled proliferation and invasion. 23 , 24 In parallel, more recent reviews have expanded this perspective by highlighting the broader role of ion‐channel‐mediated bioelectric signalling in tumour progression, therapy resistance, and microenvironmental interactions. 50 , 51

Meanwhile, developmental and systems biology research has introduced bioelectricity as a fundamental regulator of cell fate, tissue patterning, and morphogenesis. Reviews by Levin and colleagues have been particularly influential in establishing the membrane potential as an instructive signal that can control large‐scale pattern formation and long‐range cellular communication. 1 , 2 Within this framework, V m is understood not merely as a passive biophysical parameter, but as an active regulator of cellular decision‐making. More recent work has further reinforced this concept by linking bioelectric signalling to multiscale regulatory processes and disease states, including cancer. 50 , 52

More recently, emerging reviews have begun to reconcile these different approaches to cancer. For instance, Yang and Brackenbury emphasised the significance of membrane potential in cancer progression and proposed it as a potential therapeutic target, 3 , 13 while Payne et al. highlighted the importance of bioelectric control mechanisms in metastasis. 15 These contributions represent important steps towards integrating bioelectricity into oncology and are complemented by recent efforts to position bioelectric signalling within translational and therapeutic frameworks. 50 , 51

However, despite these advances, the literature remains fragmented across three largely separate domains. Firstly, reviews focusing on cancer predominantly analyse individual ion channels or channel families without considering their collective impact on membrane potential at a systems level. 23 , 24 Secondly, reviews focusing on bioelectricity mainly address development and regeneration, with limited application to tumour biology or clinical oncology. 1 , 2 Thirdly, discussions of translation often highlight therapeutic opportunities but lack quantitative frameworks for V m measurement, standardisation, and clinical implementation. 13 , 15

Consequently, membrane potential is often treated as a secondary parameter, not as a primary organising principle of cancer cell behaviour. This fragmentation limits both mechanistic understanding and translational progress. 3 , 18 , 23

This review addresses these issues by adopting a systems‐level perspective, positioning V m as an integrative state variable that links ion‐channel activity, signalling networks, metabolism and cell‐state transitions. Unlike prior reviews that primarily focus on individual ion channels or conceptual aspects of bioelectricity, this work introduces V m as a quantitatively comparable, system‐level state variable and explicitly links mechanistic evidence to a structured translational framework.

By explicitly connecting mechanistic insights with clinical applicability, this work aims to advance the field from descriptive observations to a structured, testable bioelectric paradigm in cancer research. Remaining gaps include cross‐tumour quantitative V m comparisons and clinical standardisation, as well as the development of predictive, attractor‐based, multiscale models that can link bioelectric state transitions to therapeutic decision‐making. 31 , 32 , 53 , 54 , 55