Bacteria-based biohybrids for remodeling adenosine-mediated immunosuppression to boost radiotherapy-triggered antitumor immune response.

Abstract

Radiotherapy (RT) can trigger immunogenic cell death (ICD) in tumor cells and release adenosine triphosphate (ATP) to activate antitumor immunity. However, the formation of immunosuppressive adenosine (ADO) mediated by ectonucleotidases including CD39 and CD73, can exacerbate the immunosuppressive effects. Herein, a radiosensitizer-based metal-organic framework (MOF) composed of bismuth (Bi) and ellagic acid (EA) was synthesized in situ on the surface of Escherichia coli Nissle 1917 (EcN) to serve as a carrier for the CD39 inhibitor sodium polyoxotungstate (POM-1). This therapeutic platform, acting as a radiosensitizer, significantly enhances cytotoxicity against tumor cells while effectively inducing ICD and releasing high concentrations of ATP. Subsequently, the released POM-1 increases the levels of pro-inflammatory extracellular ATP while preventing tumor immunosuppression caused by the accumulation of ADO. Additionally, as a natural immune adjuvant, EcN further promotes the maturation of dendritic cells (DCs) and the infiltration of cytotoxic T lymphocytes (CTLs). As a result, such treatment initiates the destruction of established tumor growth and induces strong abscopal effects, leading to a significant inhibition of tumor metastases. This strategy presents a bacterial-based biohybrid system that facilitates RT-induced ICD while simultaneously limiting the degradation of ATP into ADO, thereby achieving sustained anti-tumor immunity.