Photoelectrical control of apoptosis and autophagy

Controlling cancer cell fate through membrane depolarization, reactive oxygen species (ROS) dynamics, and voltage-gated ion channel (VGIC) activation represents a rapidly advancing paradigm in bioelectronic oncology. Electrically excitable cancer cells-including glioblastoma, retinoblastoma, SH-SY5Y neuroblastoma, MCF-7, and MDA-MB-231-exhibit distinct electrophysiological and redox sensitivities that govern their responsiveness to photoelectrical stimulation. Here, we develop an integrated theoretical and transcriptomic framework describing how photocapacitive and photofaradaic stimulation modulates intracellular calcium signaling, mitochondrial membrane potential (ΔΨm), and ROS homeostasis to determine apoptotic, autophagic, or proliferative outcomes. Experimental data sets from GSE59612, GSE103224 (glioblastoma), GSE97508 (retinoblastoma), and GSE45827 (breast cancer) parameterize VGIC families, antioxidant pathways, and cell death modules. New simulations using a measured 20-Hz photovoltaic waveform show that photocapacitive depolarization elevates glioblastoma ROS levels to ∼150-160 μM over 30 min, placing cells within a proliferative-to-autophagic transition region, with a small apoptotic component. Mapping these ROS trajectories to a bifurcation-based cell fate model reveals glioblastoma-specific redox thresholds that align with transcriptomic VGIC and antioxidant signatures. By unifying stimulation physics, bioelectrical modeling, and omics-based parameterization, this work provides a predictive foundation for designing photovoltaic cancer therapies tuned to cell-type-specific electrophysiological and redox landscapes. Moreover, in MDA-MB-231 cells the same stimulation induces a controlled, early-stage autophagy response, providing an intrinsic antiinflammatory benefit that can suppress early tumorigenic signaling.