Chemical Modulation of Glucose Metabolism with a Fluorinated CaCO₃ Nanoregulator Can Potentiate Radiotherapy by Programming Antitumor Immunity

Abstract

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 (fCaCO3) nanoregulator by coating CaCO3 nanoparticles with dopamine-grafted perfluorosebacic acid (DA2-PFSEA) and ferric ions by utilizing their coordination interaction. After PEGylation, the obtained fCaCO3-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@fCaCO3-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@fCaCO3-PEG could improve the therapeutic outcome of radiotherapy toward two murine tumors with distinct immunogenicity. The PFCE@fCaCO3-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 CaCO3 nanoregulators to reverse tumor immunosuppression and potentiate radiotherapy through chemically modulating tumor hypoxic and acidic microenvironments tightly associated with tumor glucose metabolism.

Nanotechnological strategies to increase the oxygen content of the tumor

“…In perfluorocarbons, oxygen undergoes physical dissolution, and there is a weak non-directional van der Waals force between oxygen and perfluorocarbons, which also ensures that oxygen can be dissolved or released quickly. Various perfluorocarbon (PFC)-based oxygen delivery nanoplatforms, such as liposomes, hollow nanomaterials or polymers, have been successfully fabricated and utilized to alleviate tumor hypoxia and enhance oxygen-related therapeutic efficacy ( Cheng et al, 2015 ; Gao et al, 2017 ; Li et al, 2018 ; Liang et al, 2020 ; Dong et al, 2022 ). However, the premature release of oxygen before reaching the anoxic region and the oxygen transport mainly driven by the concentration gradient are not controllable.…”

Oxygen-carrying nanoplatform to reprogram tumor immunosuppressive microenvironment and enhance photothermal-immunotherapy

“…As tumor hypoxia is a driving force in immunosuppressive TME [ [21] , [22] , [23] , 49 ], the potency of IR-R@LIP/PFOB in reversing the immunosuppressive state was then evaluated. After that, we carefully investigated the influence of IR-R@LIP/PFOB in combination with PTT treatment on the differentiation of TAMs polarization within tumors.…”

“…However, as a hallmark of the tumor, hypoxia has been reported to increase some immunosuppressive components, such as regulatory T cells (Tregs), related immunosuppressive cytokines, and tumor-associated macrophages (TAMs) [ [21] , [22] , [23] ]. TAMs are the most abundant immune cells in the TME, and are closely related to metastasis, angiogenesis and immunosuppression [ 24 , 25 ].…”

“…Therefore, hypoxia can significantly exacerbate the immunosuppressive TME and accelerate tumor progression and metastasis. Inarguably, the alleviation of hypoxia is essential for the implementation of immunotherapy, and efficient oxygen delivery could be the cure [ [21] , [22] , [23] ]. Among various oxygen delivery strategies, perfluorocarbon has been found to be an ideal platform for hypoxia attenuation.…”

Modification of erythrocytes by internalizing Arg-Gly-Asp (iRGD) in boosting the curative effect of radiotherapy for gastric carcinoma

“…In recent years, a considerable amount of research on the resistance and sensitization of tumor RT, chemotherapy, immunotherapy, and targeted therapy has emerged, especially in the field of nanomaterials and small biological molecules (23)(24)(25)(26). In our team's previous work, we successfully constructed the recombinant protein iRGD- antiCD3 and demonstrated its antitumor efficacy by promoting T cell activation and infiltration.…”