Bioelectromagnetic reprogramming of tumor-immune metabolism to selectively destroy NSCLC

BACKGROUND: Dysregulated oxygen and redox-active metal metabolism create an oxidized tumor microenvironment in non-small cell lung cancer (NSCLC). Tumors accumulate reactive oxygen species (ROS) and labile iron, promoting progression yet creating a vulnerability to iron-catalyzed ROS and lipid peroxidation. This oxidized microenvironment also alters tumor-immune metabolic balance, impeding immune function in the TME. Existing electromagnetic-based therapies such as tumor treating fields and electroporation do not directly target redox-metabolic vulnerabilities and have usability constraints. Building on our recent work published in Cell Metabolism showing that orthogonally applied static electromagnetic fields (EMFs) safely reprogram redox and glucose metabolism to treat diabetes, we sought to determine whether a bioelectromagnetic modality applied during convenient treatment times could be engineered to reprogram tumor-immune metabolism for selective killing of NSCLC. METHODS: We engineered a device to deliver orthogonally oriented static EMFs for ≥6 hours / day. Mice bearing human NSCLC xenografts (H1299 & A549) or syngeneic LLC tumors were randomized to EMF or sham. Tumor growth, survival & combination with chemoradiation therapies were evaluated. Mechanistic studies assessed lipid peroxidation, gammaH2AX, T-cell activation/exhaustion & antigen-specific CD8⁺ trafficking, CD4⁺/CD8⁺ depletion, and effects of scavenging H₂O₂, labile iron, or lipid peroxides on ferroptotic pathways. Histopathology assessed toxicity. RESULTS: EMF monotherapy inhibited tumor growth & prolonged survival versus sham and improved chemoradiation efficacy. EMF-treated tumors showed increased lipid peroxides and gammaH2AX, consistent with lipid peroxidation and DNA damage induced tumor death. In syngeneic tumors, EMF enhanced CD8⁺ and CD4⁺ T-cell activation and reduced exhaustion. OT-I and T-cell depletion studies showed EMF efficacy requires antigen-specific adaptive immunity. Genetic scavenging of H₂O₂, iron, or lipid peroxides within tumors attenuated EMF-induced tumor killing, demonstrating ferroptotic tumor death without normal-tissue toxicity. CONCLUSIONS: Orthogonally applied static EMFs represent a novel bioelectronic strategy to selectively kill NSCLC by exploiting redox-metabolic vulnerabilities and activating antitumor immunity. This bioelectronic modality could be used to safely enhance tumor killing while overcoming adherence challenges of existing field-based modalities.