Abolishing extracellular breast intratumoral bacteria-mediated immunosuppression and chemo-immunotherapy tolerance with spatiotemporal polyprodrug
Treatment resistance fuels breast cancer recurrence and poor prognosis. This study identified enterotoxigenic Bacteroides fragilis (ETBF) enrichment in breast cancer tissues, which correlated with suppressed anti-tumor immunity and chemo-immunotherapy tolerance. Mechanistically, ETBF-secreted Bacteroides fragilis toxin (BFT) exacerbates NAD(P)H Quinone Dehydrogenase 1 (NQO1)-mediated metabolic dysregulation, thereby impairing immune surveillance and compromising therapeutic efficacy. Given that ETBF colonizes extracellular hypoxic niches, we designed hypoxia-responsive polyprodrug nanoparticles (PolyOxa-azo-MTZ NP) that exert spatiotemporal antibacterial activity prior to chemo-immunotherapy administration. In murine models, these nanoparticles targeted hypoxic tumor regions, eradicated ETBF within 24 hours, downregulated NQO1 to reverse metabolic reprogramming, restored anti-tumor immune function, and augmented treatment responses. Collectively, our work establishes ETBF as a key microbial mediator of therapeutic resistance via its induction of NQO1-driven metabolic dysregulation, and presents a dual-targeting strategy that coordinates spatiotemporal antibacterial and anticancer actions to overcome such resistance, advancing the paradigm of microbiota-inspired cancer therapy.