Amodiaquine Enhances Anti‐Melanoma Efficacy of Attenuated Salmonella via Targeting Glutathione Reductase in Neutrophils

ABSTRACT Attenuated Salmonella VNP20009 (VNP) induces significant neutrophil recruitment in the tumor microenvironment (TME) during cancer therapy. However, the exact role of neutrophils in VNP‐mediated antitumor effects remains elusive. Here, we first identified the recruited neutrophils as predominantly N2 (pro‐tumor) subtype, which remarkably compromised VNP's antitumor efficacy. Therefore, we combined amodiaquine (AQ), known for its neutrophil‐inhibiting activity, with VNP treatment to enhance antitumor effects. The combination selectively inhibited TME neutrophils while maintaining favorable biosafety profiles. Employing chemical biology approaches, we identified glutathione reductase (GR) as the key target in neutrophils. Mechanistically, AQ binds to GR and compromises neutrophils' ROS tolerance, leading to selective elimination of neutrophils in the high‐ROS TME. A GR‐shRNA‐loaded VNP strain was further engineered and significantly potentiated VNP's antimelanoma effects. Our work not only advances the understanding of VNP‐immune‐tumor crosstalk but also provides a potential translational strategy that integrates drug repurposing with synthetic biology for developing microenvironment‐smart therapeutics.