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.