A bioimpedance-guided computational framework for investigating frequency shifts in tumor treating fields therapy

Tumor Treating Fields (TTFields) therapy applies intermediate-frequency alternating electric fields to disrupt tumor-cell proliferation. Although its effects are frequency-dependent, current clinical protocols commonly rely on fixed, empirically selected frequencies that may not fully capture treatment-related changes in tumor-cell dielectric properties over the course of prolonged therapy. Here, a lumped-parameter equivalent-circuit model of a cell suspension was used to quantify how defined changes in effective cell-suspension electrical properties are expressed as impedance-derived β-dispersion spectral shifts within a TTFields-relevant frequency range. Complex impedance was simulated over 1-500 kHz, and two complementary descriptors were extracted: the Nyquist-peak frequency and the phase-minimum frequency. Their baseline values were 179.1 kHz and 249.1 kHz, respectively; however, their correspondence with the TTFields frequency range reflects the selected baseline parameters and does not constitute experimental validation. Over the ±30% range, variation in membrane capacitance shifted the Nyquist-peak and phase-minimum frequencies by up to 76 and 106 kHz, respectively, and produced the largest mean absolute shift for both descriptors. Coupled variation of membrane capacitance and intracellular resistance demonstrated that identical frequency shifts can arise from different parameter combinations, precluding unique inverse attribution from either descriptor alone within the evaluated parameter space. Application of published cell-suspension parameter sets provided external spectral consistency but did not constitute direct validation under TTFields exposure conditions. These findings support interpreting the Nyquist-peak and phase-minimum frequencies as complementary computational descriptors of changes in the modeled impedance response and provide a basis for further experimental investigation using time-resolved electrical impedance spectroscopy during TTFields exposure.