Adaptive Closed-Loop Bioelectric Control of Cancer Cell Phenotype: A Navigation-Based Framework and Experimental Roadmap

Cancer cells are consistently depolarized (resting membrane potential Vmem ≈−10 to −30mV) relative to healthy differentiated cells (Vmem ≈ −60 to −90mV),and gap junctional intercellular communication (GJIC) is disrupted in most solidtumors. In model organisms these bioelectric changes have been shown to causallycontribute to the malignant phenotype: artificial depolarization of normal cellsinduces neoplastic behavior, while forced hyperpolarization suppresses oncogenedriventumorigenesis. Existing bioelectric interventions are open-loop—a stimulusis applied and the outcome observed post hoc. Here we propose the AdaptiveClosed-Loop Bioelectric Navigator (ACBN), an integrated sensing–computation–intervention platform that continuously monitors cellular bioelectricstate, classifies the mode of dysregulation using a proposed four-category framework(KIND), and delivers targeted micro-corrections through multiple channels in aclosed-loop feedback architecture. We illustrate the control logic using Neural CellularAutomata as a synthetic test system and present a concrete, low-cost (∼$10,000)experimental protocol for in vitro validation using MCF-7 breast cancer cells, includinginternal calibration procedures, phototoxicity assessment, cross-validationwith multiple hyperpolarizing agents, single-cell analysis, and explicit falsificationcriteria. We do not claim that bioelectric modulation alone is sufficient for cancertreatment; rather, we propose that closed-loop bioelectric control represents anunderexplored therapeutic layer that may complement existing approaches. Thecentral open question—whether bioelectric normalization can produce durable phenotypicreversal in human cancer cells—is experimentally testable and constitutesthe primary falsification criterion for this framework.