Cancer: A bioelectric disease?
However, the relationship between V m and metastasis is not strictly linear. Context‐dependent effects have been reported, such as hyperpolarisation suppressing proliferation but enhancing migratory capacity, and depolarisation reducing metastatic dissemination under certain conditions. 15 , 44 , 46 , 74 , 75 These findings suggest that migration is influenced not only by absolute V m values, but also by the interaction between ion fluxes, the cell cycle and the microenvironment.
In summary, the membrane potential acts as a regulator of metastatic competence, integrating bioelectric, mechanical, and biochemical processes. V m defines a dynamic state space that enables cancer cells to transition between proliferative and migratory phenotypes, beyond simple promotion or inhibition of invasion. Targeting this bioelectric plasticity may therefore be a way to disrupt metastatic progression and limit tumour spread.
Although numerous studies have centred on V m at the level of individual cells, emerging evidence suggests that cancer bioelectricity functions as a multicellular and network‐level phenomenon. Tumours are electrically coupled systems, not merely collections of independent cells, in which coordinated V m dynamics can propagate across cell populations and influence collective behaviour. 1 , 11 , 12 , 31 , 33 , 61 , 77 In addition to breast cancer and glioma, intrinsic electrical activity has also been associated with the progression of small‐cell lung cancer, providing further support for the idea that electrical signalling can drive malignancy in certain tumour types. 52
High‐resolution voltage imaging studies have demonstrated that cancer cells exhibit temporally correlated dynamic V m fluctuations across spatially separated cells. 60 In breast cancer models, these fluctuations manifest as recurrent hyperpolarisation spikes and wave‐like propagation patterns, which are absent in non‐malignant epithelial cells. 60 Such coordinated electrical activity suggests the presence of bioelectric communication networks, which are mediated by gap junctional coupling and local electric field interactions. Gap junctions, which are primarily formed by connexin proteins, provide direct cytoplasmic coupling between adjacent cells, enabling the propagation of electrical and ionic signals across tumour cell populations. Altered connexin expression and function have been widely reported in cancer and can disrupt intercellular communication, contributing to tumour progression, heterogeneity, and resistance. 22 , 23 , 24 In this context, gap junctional coupling is a vital mechanism through which local changes in membrane potential can spread across tissues, facilitating coordinated bioelectric patterning at the multicellular level. 11 , 12
These network‐level dynamics provide a rapid, non‐diffusive mechanism for information transfer within tumours, complementing classical biochemical signalling pathways. Unlike paracrine or autocrine signalling, which rely on molecular diffusion, bioelectric signals can propagate over larger distances and in shorter timescales. This enables the synchronisation of cellular states, such as proliferation, migration and differentiation. 31 , 32 , 73
In addition to tumour‐tumour communication, interactions between cancer cells and electrically active host tissues further expand the bioelectric network. In glioblastoma, for instance, tumour cells establish functional synaptic connections with neurons, enabling neuronal activity to depolarise cancer cells directly. 61 This neuron‐to‐tumour signalling induces sustained depolarising currents and enhances tumour proliferation. Conversely, tumour cells can increase neuronal excitability through glutamatergic signalling, thereby establishing a bidirectional feedback loop that amplifies disease progression. 52 , 61 , 77
At the tissue level, these interactions imply that tumours integrate into pre‐existing bioelectric circuits, hijacking physiological signalling networks to promote malignant growth. This reframes cancer progression as an emergent property of coupled cellular systems, not a purely cell‐autonomous process. 61 , 77
Importantly, network‐level bioelectricity also enables long‐range control of tumour behaviour. Experimental models have demonstrated that bioelectric perturbations in one region of tissue can influence tumour formation at distant sites, indicating that V m‐mediated signalling can operate across spatial scales beyond individual tumours. 3 , 11 , 12 These findings are consistent with the concept of bioelectric fields acting as organising signals that coordinate cellular behaviour across tissues. This is in line with earlier hypotheses that linked membrane potential, sodium channels and gap junctions to growth regulation and tumour formation. 7
These observations establish the membrane potential as a mediator of collective tumour behaviour, integrating single‐cell electrophysiology with tissue‐level organisation. V m dynamics can synchronise malignant phenotypes, amplify signalling cascades and couple tumour cells to their microenvironment. This network perspective provides a conceptual framework for understanding how local bioelectric dysregulation can lead to systemic disease progression. 31 , 32 , 50
From a translational perspective, targeting bioelectric coupling by modulating gap junctions, ion channels or applying external electric fields may disrupt tumour coordination and reduce collective behaviours such as invasion and resistance to therapy. Therefore, incorporating network‐level bioelectricity into experimental and computational models will be essential for capturing the full complexity of cancer as a bioelectric system. 23 , 53 , 78 , 79
One of the key mechanisms through which V m influences immune regulation is calcium signalling. The activation of T lymphocytes critically depends on sustained Ca2 + influx, driven by electrochemical gradients across the plasma membrane. Ion channels maintain the membrane potential, thereby regulating the driving force for Ca2 + entry through CRAC/Orai1 channels. Depolarising conditions can reduce this driving force, thereby impairing T cell activation, cytokine production and proliferation. 23 , 29 , 80 , 81
Notably, the tumour microenvironment is characterised by altered ionic conditions, including elevated extracellular potassium and sodium levels. These conditions can depolarise infiltrating immune cells and suppress their effector functions. These bioelectric alterations are consistent with the broader phenomenon of ion‐channel remodelling in cancer and its impact on cellular behaviour. 23 , 24 , 29
Beyond T cells, ion‐channel‐mediated membrane potential regulation may also influence macrophage polarisation. Distinct ionic and metabolic states are associated with pro‐inflammatory (M1‐like) and anti‐inflammatory (M2‐like) phenotypes, suggesting that bioelectric signals may contribute to shaping tumour‐associated immune responses. However, direct causal evidence remains limited. 23 , 29 , 80 , 81
From a translational perspective, these mechanisms imply that bioelectric modulation could enhance immunotherapy. Immune checkpoint pathways are closely linked to calcium signalling and metabolic state, and V m‐dependent modulation of Ca2 + dynamics may influence T cell activation and exhaustion. Therefore, modulating tumour or immune cell V m could improve the efficacy of immune checkpoint inhibitors by restoring Ca2 +‐dependent activation pathways and reversing tumour‐induced immunosuppression. 23 , 29 , 68 , 80 Figure 2 summarises the membrane potential (V m) networks in cancer.
The ability to measure and manipulate V m sets bioelectricity apart from many other cancer‐relevant parameters, providing a direct link between mechanistic insight and clinical application. Unlike static molecular alterations, V m is a dynamic, reversible and tuneable state variable that can function as a diagnostic biomarker, a pharmacodynamic readout and a therapeutic control target simultaneously. 13 , 34 , 50 , 51 , 60 , 82 , 83
A large body of experimental research has examined the role of membrane potential in tumour development in various model systems. These studies provide a biological basis for understanding how V m regulates cancer‐associated phenotypes. Table 2 summarises key studies examining V m in tumour initiation, proliferation and differentiation, and includes comparisons with healthy cells.
These studies demonstrate that depolarised membrane potentials are consistently associated with proliferative, stem cell‐like and therapy‐resistant states. Conversely, hyperpolarisation is often associated with differentiation and growth suppression, suggesting that V m plays a functional role beyond that of a purely descriptive parameter. These mechanistic insights have led to the exploration of a wide range of strategies to modulate membrane potential for therapeutic purposes.
Table 3 provides an overview of pharmacological, genetic and physical interventions targeting V m, together with the observed effects of these interventions on tumour behaviour and the reported selectivity of the interventions.
These studies demonstrate that membrane potential is a measurable biomarker and a controllable variable. However, the effects of V m modulation are highly context‐dependent, emphasising the importance of state‐aware therapeutic strategies that consider tumour type, cell‐cycle phase and microenvironmental interactions.
A key translational opportunity lies in using V m as a functional biomarker of the malignant state. Experimental studies have shown that depolarisation can precede detectable morphological transformation and predict tumour formation with a level of performance comparable to that of established molecular markers in controlled models. 6 , 12 , 60 This suggests that V m may provide an early functional readout of tumourigenic state transitions.
Advances in voltage‐sensitive dyes, genetically encoded voltage indicators and fluorescence lifetime imaging now enable the high‐resolution, quantitative mapping of V m in live cells and tissues. 60 , 83 , 98 , 99 , 100 These approaches allow discrimination between malignant and non‐malignant cells based on their electrical signatures, enabling the detection of dynamic V m fluctuations associated with aggressive behaviour.
In a translational context, integrating V m measurements into ex vivo biopsy workflows could provide rapid orthogonal information alongside histopathology and genomic profiling. Intraoperative V m mapping could further improve tumour margin assessment, while longitudinal V m monitoring could serve as a pharmacodynamic biomarker to evaluate treatment response in real time. However, achieving clinical applicability will require the standardisation of calibration protocols, dye performance and measurement conditions to ensure reproducibility and comparability across studies. 60 , 83 , 98 , 100
Pharmacological modulation of V m is a versatile strategy for reshaping malignant bioelectric states. A variety of ion channel modulators, such as potassium channel activators, sodium channel blockers and synthetic anion transporters, have been demonstrated to affect the proliferation, differentiation and apoptosis of cancer cells. 5 , 14 , 38 , 70 , 74 , 86 , 89 , 101 In many cases, enforced hyperpolarisation suppresses proliferation and promotes differentiation, particularly in cancer stem cell‐like populations.
Importantly, V m modulation can also act as a sensitisation strategy. Controlled depolarisation has been shown to increase susceptibility to agents that induce apoptosis, such as TRAIL, by altering mitochondrial function and calcium dynamics. 92 These findings suggest that bioelectric interventions could complement existing therapies by rendering tumour cells more susceptible to treatment. Studies showing that depolarisation can potentiate TRAIL‐induced apoptosis also support this sensitisation concept, thereby reinforcing its therapeutic relevance. 91 , 102
Genetic approaches provide additional specificity and mechanistic insight. Optogenetic tools enable the precise and reversible control of V m via light‐driven ion transport, facilitating the direct investigation of the causal relationships between membrane potential and tumour behaviour. 51 Similarly, engineered ion channels can selectively target cancer cells based on their bioelectric properties, inducing apoptosis or growth arrest without affecting surrounding healthy tissue. 93 These strategies highlight the potential for highly controlled, spatially restricted bioelectric interventions. In addition, repurposing clinically established ion‐channel drugs, including antiarrhythmics, alongside broader V m‐modulating strategies targeting potassium, sodium and calcium channels remains an attractive route for translation, although potential electrophysiological side effects must be carefully considered. 23 , 24 , 33 , 38 , 46 , 50 , 94 , 95 , 103
The translational interpretation of several V m‐modulating compounds also depends on existing pharmacological and safety knowledge from non‐oncology contexts, including antiarrhythmics, 4‐aminopyridine, paclitaxel and hydrogen sulphide donors. 70 , 87 , 88 , 94 , 95 , 104 , 105 Toxicity considerations for compounds such as hydrogen sulphide donors further illustrate the importance of dose‐dependent safety evaluation. 88
Physical approaches offer clinically scalable methods of modulating V m that do not rely on systemic pharmacology. Tumour‐treating fields (TTFields) are the most advanced example and have an established clinical use in the treatment of glioblastoma and mesothelioma. 78 , 79 , 82 , 106 Although their mechanisms are still being investigated, accumulating evidence suggests that TTFields disrupt membrane potential dynamics and ion‐channel activity, thereby contributing to anti‐proliferative and pro‐apoptotic effects. 78 , 79 , 96 , 106 , 107
Theoretical and experimental studies suggest that cancer cells may experience greater V m fluctuations under alternating electric fields due to variations in membrane properties, size, and dielectric characteristics. This differential sensitivity may contribute to the tumour selectivity observed with TTFields, suggesting that bioelectric vulnerabilities can be exploited through externally applied fields. 98 , 101 , 106
Alongside electromagnetic approaches, charged nanomaterials and electroactive compounds have emerged as tools for manipulating membrane potential and cellular behaviour. These materials interact with the plasma membrane via electrostatic mechanisms, thereby influencing ion flux, intracellular signalling and drug uptake. 84 , 90 While the exact contribution of V m modulation versus secondary effects is yet to be fully resolved, these methods demonstrate the wider potential of bioelectric engineering in oncology. 84 , 90 , 108 , 109
Despite promising experimental and early translational results, there are several challenges that must be addressed before V m can be fully integrated into clinical oncology. One major limitation is the lack of standardised, high‐throughput methods for measuring membrane potential in patient samples. Although patch‐clamp electrophysiology is still considered the gold standard, it is not easily scalable, so robust optical or indirect measurement techniques that are suitable for clinical workflows must be developed. 83 , 98 , 100