Engineered bacteria reverses tumor cuproptosis resistance via cancer-associated fibroblast reprogramming for enhanced immunotherapy

Abstract

Cuproptosis, a novel modality of mitochondrial copper-induced cell death, holds great therapeutic potential against cancer. However, its efficacy is limited by cancer-associated fibroblasts (CAFs), which confer the cuproptosis resistance in tumor by upregulating the copper exporter ATP7A. In this study, we developed an engineered bacteria system, PCuS-MG, for synergistic cuproptosis and immunotherapy via CAFs reprogramming. PCuS-MG consists of E. coli MG1655 modified with pirfenidone-loaded copper sulfide nanoparticles. Upon intravenous administration and 1064 nm laser irradiation, PCuS-MG accumulates in tumors and releases Cu2+ and pirfenidone. The released Cu2+ synergistically triggers cuproptosis. Meanwhile, pirfenidone reprograms CAFs via TGF-β signaling inhibition and glucose metabolism modulation, thereby downregulating tumor ATP7A to reduce cuproptosis resistance. In a triple-negative breast cancer model, PCuS-MG potently inhibited primary and distant tumor growth and suppressed lung metastasis by remodeling the immune microenvironment. This study reveals the pivotal role of CAFs in cuproptosis resistance and introduces PCuS-MG as a novel platform that synergizes metal ion-induced death with CAFs reprogramming, offering a promising strategy for tumor therapy.