Microbiota-directed lactic acid depleting nanoenzyme reactivates antitumor immunity and chemosensitivity in hypoxic tumor

The acidification of the tumor microenvironment (TME) remains a major obstacle contributing to malignant progression and impeding therapeutic development. While traditionally attributed to anaerobic glycolysis, increasing evidence suggests that hypoxia-induced colonization of intratumoral symbiotic microbiota, particularly anaerobes, produce lactic acid (LA) metabolites serves as a significant contributor to TME acidification. Although antibiotic-based combination therapies have been explored for the hypoxic tumor treatment, the efficiency was restricted in reversing acidification-induced immunosuppression and chemoresistance. To tackle this challenge, we engineered a delivery platform (TML NPs) for lactate oxidase (LOX) and chemotherapeutic drug tirapazamine (TPZ) by modifying the carrier with metronidazole (MTZ), an antibiotic bearing hypoxia-responsive functional group. By directly targeting the symbiotic anaerobic bacterial metabolism, this strategy introduces a novel paradigm for modulating TME acidification, reversing the LA-mediated suppression of anti-tumor immune responses and chemosensitivity. Our strategy offers a promising translational platform for the precise treatment of TNBC and other hypoxic malignancies.