Reversal of the neutrophil barrier for potentiating immune-engineered bacteria therapy in pancreatic cancer.

Abstract

Engineered bacterial therapy holds the potential to overcome drug delivery barriers; remodel the immunosuppressive tumor microenvironment; and enable precise, sustained drug release within tumors. However, after infiltrating the tumor, engineered bacteria extensively recruit neutrophils, which directly phagocytose and eliminate the bacteria, confining them to the necrotic core and impeding their migration toward proliferative tumor regions, thereby limiting therapeutic efficacy. In this study, we introduce indole-3-acetic acid as an adjuvant to bacterial therapy. Note that, indole-3-acetic acid directly suppresses neutrophil recruitment. Simultaneously, it synergizes with gemcitabine to eliminate existing neutrophils. Experiments demonstrate that this method promotes intratumoral colonization, enhances immune activation efficiency, and can significantly reduce the clearance of therapeutic bacteria in pancreatic cancer mouse models. Taking PD-L1 antibody-expressing engineered bacteria as an example, the combination further strengthens T-cell-mediated antitumor immune responses through synergistic immune checkpoint blockade, ultimately achieving remarkable tumor growth suppression.