Translating physical stress into biological signals: precision electro-oncology based on conformational changes of...

Tumor Treating Fields (TTFields) and pulsed electric fields (PEF) have emerged as a fourth modality in oncological treatment, succeeding surgery, radiotherapy, and pharmacotherapy. However, the fundamental mechanisms through which physical electrical stress is precisely transduced into biochemical signals remain to be fully elucidated. By integrating molecular dynamics simulations, multi-omics profiling, and the latest clinical trial data, this review systematically explores how electric fields, functioning as physical signals, initiate intracellular transduction by inducing conformational kinetic changes in G protein-coupled receptors (GPCRs), such as NPFFR2. Furthermore, we discuss how the modulation of waveform parameters enables the precise programming of apoptosis and pyroptosis patterns, thereby inducing immunogenic cell death (ICD) and activating the cGAS-STING pathway. Additionally, proteomics-based insights are employed to reveal the mechanisms of electric-field-induced compensatory resistance, and the pivotal role of electric fields in remodeling the tumor immune microenvironment and reversing resistance to immune checkpoint inhibitors is discussed. This review aims to provide refined theoretical guidance for the clinical translation of the emerging field of the "electro-immunome".