Objective:

To explore how electric fields initiate intracellular transduction by inducing conformational changes in GPCRs and to discuss their role in immunogenic cell death and immune microenvironment remodeling.

Approach:

• Integration of methodologies: The review integrates molecular dynamics simulations, multi-omics profiling, and clinical trial data.
• Mechanistic exploration: It examines the transduction of physical electrical stress into biochemical signals and the modulation of cell death patterns.

Key Findings:

• Electric fields trigger signaling through GPCR conformational changes, such as NPFFR2.
• Waveform parameters can selectively induce apoptosis or pyroptosis.
• Electric stress activates the cGAS-STING pathway, converting tumors to a 'hot' state.
• Multi-omics profiling identifies PARP1 and BRD4 as nodes in compensatory resistance.

Interpretation:

The findings suggest that electric fields have complex biological effects beyond mere physical interference, influencing both cellular signaling and immune responses.

Limitations:

• The adaptive evolution of tumor cells under electrical stress may lead to resistance.
• Chronic exposure to electric fields may induce compensatory mechanisms that need further investigation.

Conclusion:

The review provides a theoretical foundation for the clinical translation of electro-oncology.