Dose‐dependent induction of epithelial‐mesenchymal transition in <scp>3D</scp> melanoma models by non‐thermal plasma treatment

Despite the promising results of non-thermal plasma (NTP) devices for cancer therapy, the potential adverse effects of NTP irradiation have remained unexplored, including the effects on epithelial-mesenchymal transition (EMT) and subsequent cancer metastasis. In this study, we investigate NTP-induced EMT initiation and progression. A microsecond-pulsed dielectric barrier discharge plasma device was used for NTP treatment, and chicken chorioallantoic membrane (CAM) and spheroids were used as 3D tumor models. NTP treatment reduced tumor volume in the CAM model, but a shift towards a mesenchymal-like phenotype was also measured in melanoma tumors via analysis of the six EMT biomarkers, though changes in cancer cell migration to other organs were not significant. In the spheroid model, molecular analysis also indicated an EMT response following NTP treatment, and enhanced cell migration was measured in one cell line. EMT induction with NTP was dose-dependent and transient; high NTP treatments caused significant EMT response and enhanced migration, but low NTP doses did not. Our findings highlight the important role of NTP parameters for cancer treatment and consequential EMT responses. The insights obtained here further build the foundation for clinical optimization, harnessing the cancer-killing potential of NTP while safeguarding against undesirable EMT-related outcomes.