Photothermal therapy synergizes with bacterial azurin to suppress CT26 tumor growth.

Abstract

Photothermal therapy (PTT) has emerged as a promising antitumor modality; however, the inflammatory response triggered by PTT promotes the infiltration and activation of immune cells within the tumor microenvironment, leading to elevated IFN-γ secretion. This inflammatory cytokine subsequently upregulates PD-L1 on tumor cells, facilitating tumor immune evasion and limiting the long-term efficacy of PTT. To address these challenges, we engineered a living platform (PMEA) by coating Escherichia coli Nissle 1917(ECN)with a polydopamine-metformin(MET) layer and incorporating a heat-inducible azurin circuit. Critically, we employed a two-step thermal regimen: a mild pre-heating phase (42 °C) to trigger robust azurin production and accumulation within the tumor core, followed immediately by a medium-power ablation phase (≥45 °C). During the ablation phase, the accumulated azurin exerts an apoptotic effect on tumor cells and disrupts mitochondrial integrity, synergizing with PTT to enhance the therapeutic efficacy. Consequently, the synergistic interplay between photothermal heat and azurin-induced mitochondrial dysfunction achieves enhanced immediate tumoricidal efficiency, while the PDA@MET layer concurrently suppresses PTT driven PD-L1 upregulation. In a CT26 model, this synergistic regimen achieved >80% inhibition and significantly extended survival, providing a paradigm for spatiotemporally programmable bacteria-based combination therapy.