Medium-Frequency Electrotherapy-Driven Remodeling of Tumor Biology and Overcoming Treatment Resistance: Molecular Mechanisms and Clinical Integration.

Electrotherapy exerts antitumor effects by applying specific electric currents or fields to tumor tissues, inducing biological responses through thermal, non-thermal, and electrochemical mechanisms. In recent years, electrotherapy has emerged as a promising approach in cancer treatment. Its therapeutic efficacy is largely determined by key physical parameters, including frequency, voltage, electric field strength, and exposure duration. Among various electrotherapy modalities, medium-frequency electrotherapy, which primarily operates through non-thermal mechanisms, induces biological effects via coordinated regulation of multiple cellular processes, including membrane potential modulation, ion channel activity, and intracellular signaling pathways. This category mainly includes pulsed electric fields and tumor treating fields. This review systematically summarizes the historical development and evolution of electrotherapy, with particular emphasis on the regulatory effects of medium-frequency electrotherapy on malignant tumor biology. We further discuss the molecular mechanisms through which medium-frequency electrotherapy, alone or in combination with surgery, chemotherapy, radiotherapy, and immunotherapy, may overcome tumor treatment resistance. By integrating recent clinical evidence regarding the application of medium-frequency electrotherapy in combination with conventional anticancer therapies, this review proposes a 'physical energy-biological effect-clinical translation' framework. Through elucidating how electrotherapy reshapes tumor biology and attenuates resistance to established treatments, this review provides new insights into the development of multimodal therapeutic strategies for cancer.