Electrode material and electrical delivery mode shape the mechanisms and efficacy of electrochemical tumor ablation

Electrochemical treatment (ECT) ablates tumors by generating localized pH gradients and redox-active species at electrode-tissue interfaces, yet protocols remain poorly standardized, particularly with respect to electrode composition and delivery mode. Here, we systematically compared ECT using an inert platinum anode (ECT_Pt) or a sacrificial iron anode (ECT_Fe) under constant-current (CC) and constant-voltage (CV) conditions. In vitro, both systems produced steep anodic acidification and cathodic alkalization, but their anodic chemistries diverged. ECT_Pt generated strong oxidizing activity and caused oxidative damage, whereas ECT_Fe released Fe²⁺/Fe³⁺ and promoted ferroptosis-associated cell death. Under matched CC conditions, ECT_Pt produced stronger anodic acidification and greater cytotoxicity than ECT_Fe. Under matched CV conditions, ECT_Fe delivered progressively higher current and charge, leading to stronger cytotoxicity. Importantly, equal total charge did not yield equivalent outcomes: high-current/short-duration delivery favored ECT_Pt, whereas low-current/long-duration delivery favored ECT_Fe. In a B16 melanoma model treated in CC mode, both systems significantly inhibited tumor growth, increased tumor cell death, prolonged survival, and showed no overt systemic toxicity. Together, these findings show that electrode material and delivery mode jointly shape the electrochemical microenvironment and therapeutic response of ECT. This study provides a practical framework for selecting electrode configurations and operating conditions for electrochemical tumor ablation.