Abolishing extracellular breast intratumoral bacteria-mediated immunosuppression and chemo-immunotherapy tolerance with spatiotemporal polyprodrug
Treatment resistance drives recurrence and poor outcomes in breast cancer. Recent research has increasingly focused on exploring tumor-associated bacterial components within the biological context of breast cancer. This study identified enterotoxigenic Bacteroides fragilis (ETBF) as enriched in breast cancer tissues, where it correlated with suppressed anti-tumor immunity and chemo-immunotherapy tolerance. Mechanistically, the ETBF-secretated toxin BFT exacerbated NQO1-mediated metabolic dysregulation, impairing immune surveillance and diminishing therapeutic responses. Notably, ETBF predominantly colonized extracellular hypoxic niches. This spatial distribution inspired the design of spatiotemporal polyprodrug nanoparticles capable of hypoxia-responsive antibacterial activity prior to chemo-immunotherapy. Specifically, these nanoparticles were synthesized from oxaliplatin (OXA) prodrug-backboned polymer conjugated with hypoxia-sensitive linker-modified metronidazole (MTZ) side chains (PolyOxa-azo-MTZ NP). In murine models, they effectively targeted hypoxic tumor regions and eradicated ETBF within 24 hours. ETBF elimination led to a marked downregulation of NQO1 expression, which restored antitumor immunity and potentiated chemo-immunotherapy. Our work unveils ETBF as a key microbial mediator of resistance and provides an innovative dual-targeting strategy that spatially coordinates antibacterial and anticancer action to overcome treatment resistance, advancing the paradigm of microbiota-inspired cancer therapy.