Abstract: Tumor heterogeneity, drug resistance, and systemic toxicities severely limit the clinical efficacy of current cancer therapies, highlighting the urgent need for safer and more precise therapeutic strategies. Our previous work demonstrated that angiogenesis-targeted electric fields (ATEF), a non-invasive biophysical treatment modality, can significantly inhibit the growth of glioblastoma. Based on these findings, the present study evaluated the antitumor effects of ATEF in a non-small cell lung cancer (NSCLC) model and systematically investigated its underlying molecular mechanisms. Using a subcutaneous Lewis lung carcinoma xenograft model in C57BL/6 mice (Mus musculus) , we found that ATEF treatment markedly suppressed tumor growth without inducing significant body weight changes. Transcriptomic profiling revealed that ATEF significantly downregulated Slc7a11, a key regulator of ferroptosis, while upregulating Vldlr, a gene encoding a lipid metabolism receptor. Metabolomic analysis further demonstrated that ATEF induced pronounced remodeling of lipid and energy metabolism in tumor tissues, with multiple phospholipid species and arachidonic acid metabolic pathways being upregulated. Integrated transcriptomic and metabolomic analyses revealed that Slc7a11 was negatively correlated with membrane lipid metabolites, whereas Vldlr was positively correlated with arachidonic acid and phospholipid metabolites, suggesting that ATEF may enhance ferroptosis sensitivity by coordinately regulating oxidative stress and lipid metabolic networks, thereby interfering with angiogenesis and ultimately suppressing tumor growth. Collectively, our findings reveal that ATEF suppresses NSCLC growth by inducing transcriptional and metabolic reprogramming within the tumor microenvironment through biophysical electric field modulation, providing a mechanistic basis for further clinical translation of this novel therapeutic approach.
Keywords: angiogenesis-targeted electric fields; non-small cell lung cancer; tumor treating fields; tumor microenvironment; ferroptosis
（Acta Laser Biology Sinica, 2026, 35(3): 241-252）