Spatially programmed Fe and Pt electrode-driven electrochemistry reconditions the tumor microenvironment and sensitizes triple-negative breast cancer to PD-1 Blockade.

Excess extracellular acidity is a defining barrier to effective antitumor immunity in solid tumors. Systemic buffers only partially correct tumor acidity and seldom rescue suppressed effector immunity. Here, we developed a spatially programmed electrochemical therapy (ECTFe) integrating a central sacrificial iron anode with peripheral platinum cathodes to engineer the tumor microenvironment in situ. This configuration enables concurrent acidotoxic and ferroptosis-associated tumor debulking in the core, while controlled peritumoral pH relief restores immune cell function. We combined ECTFe with intramuscular delivery of a plasmid encoding anti-PD-1 single-chain antibody (pICI) for sustained checkpoint blockade. In aggressive 4T1-luc triple-negative breast cancer (TNBC), ECTFe markedly enhanced PD-1 blockade efficacy, inducing tumor regression and prolonged survival versus monotherapies. In B16 melanoma, ECTFe alone achieved robust tumor control with limited additional benefit from PD-1 blockade, revealing tumor-context-dependent interaction. Mechanistically, Fe-anode reactions generated an acidic, Fe2+-rich core with elevated oxidative stress and GPX4 suppression-consistent with ferroptosis-while Pt-cathode-mediated alkalinization (pH 6.6-7.0) preserved CD8+ T-cell activity, promoted M1-like macrophage polarization, and reduced regulatory T cells. Collectively, spatially programmed electrochemistry reconditions the tumor microenvironment to sensitize immunologically "cold" TNBC to PD-1 blockade, offering a controllable and translatable strategy to improve checkpoint immunotherapy.