Chemical Modulation of Glucose Metabolism with a Fluorinated CaCO 3 Nanoregulator Can Potentiate Radiotherapy by Programming Antitumor Immunity.

Tumor hypoxia and acidity are well-known features in solid tumors that cause immunosuppression and therapeutic resistance. Herein, we rationally synthesized a multifunctional fluorinated calcium carbonate (fCaCO 3 ) nanoregulator by coating CaCO 3 nanoparticles with dopamine-grafted perfluorosebacic acid (DA 2 -PFSEA) and ferric ions by utilizing their coordination interaction. After PEGylation, the obtained fCaCO 3 -PEG showed high loading efficacy to perfluoro-15-crown-5-ether (PFCE), a type of perfluorocarbon with high oxygen solubility, thereby working as both oxygen nanoshuttles and proton sponges to reverse tumor hypoxia and acidity-induced resistance to radiotherapy. The as-prepared PFCE@fCaCO 3 -PEG could not only function as long-circulating oxygen nanoshuttles to attenuate tumor hypoxia but also neutralize the acidic tumor microenvironment by restricting the production of lactic acid and reacting with extracellular protons. As a result, treatment with PFCE@fCaCO 3 -PEG could improve the therapeutic outcome of radiotherapy toward two murine tumors with distinct immunogenicity. The PFCE@fCaCO 3 -PEG-assisted radiotherapy could also collectively inhibit the growth of unirradiated tumors and reject rechallenged tumors by synergistically eliciting protective antitumor immunity. Therefore, our work presents the preparation of fluorinated CaCO 3 nanoregulators to reverse tumor immunosuppression and potentiate radiotherapy through chemically modulating tumor hypoxic and acidic microenvironments tightly associated with tumor glucose metabolism.