Coordination Polymer‐Coated CaCO₃ Reinforces Radiotherapy by Reprogramming the Immunosuppressive Metabolic Microenvironment

Abstract

Radiotherapy is widely exploited for the treatment of a large range of cancers in clinic, but its therapeutic effectiveness is seriously crippled by the tumor immunosuppression, mainly driven by the altered metabolism of cancer cells. Here, a pH‐responsive nanomedicine is prepared by coating calcium carbonate (CaCO3) nanoparticles with 4‐phenylimidazole (4PI), an inhibitor against indoleamine 2,3‐dioxygenase 1 (IDO‐1), together with zinc ions via the coordination reaction, aiming at reinforcing the treatment outcome of radiotherapy. The obtained pH‐responsive nanomedicine, coined as acidity‐IDO1‐modulation nanoparticles (AIM NPs), is able to instantly neutralize protons, and release 4PI to suppress the IDO1‐mediated production of kynurenine (Kyn) upon tumor accumulation. As a result, treatment with AIM NPs can remarkably enhance the therapeutic efficacy of radiotherapy against both murine CT26 and 4T1 tumors by eliciting potent antitumor immunity. Furthermore, it is shown that such combination treatment can effectively suppress the growth of untreated distant tumors via the abscopal effect, and result in immune memory responses to reject rechallenged tumors. This work highlights a novel strategy of simultaneous tumor acidity neutralization and IDO1 inhibition to potentiate radiotherapy, with great promises to suppress tumor metastasis and recurrence by eliciting robust antitumor immunity.

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

“…We then found that CT26 cells under acidic incubation (e.g., pH 6.5) showed increased resistance to external X-ray irradiation in comparison with those under the normal incubation (e.g., pH 7.4) (Figure C), which is consistent with previous studies . However, we found that the addition of fCaCO 3 -PEG (1.2 mM) to these CT26 cells under acidic incubation would increase their response to X-ray irradiation, indicating PFCE@fCaCO 3 -PEG could efficiently reverse tumor-acidity-induced radiotherapeutic resistance.…”

“…Radiotherapy (RT) is currently a widely used cancer treatment modality in clinics. , As a type of oxygen-consuming cancer treatment, the therapeutic efficacy of RT has been shown to be obviously restricted by limited intratumoral oxygen contents as that would limit the production of cytotoxic reactive oxygen species (ROSs), by which RT kills cancer cells. ,− Additionally, tumor acidity has also been confirmed to be a limiting factor for effective RT treatment by impairing the lifetime of these RT-generated ROSs. , With the advance of functional nanomaterials, we have witnessed the successful fabrication and utilization of diverse perfluorocarbon (PFC)-based oxygen nanoshuttles to potentiate RT treatment and other cancer treatments by utilizing their efficient oxygen-loading capacity. − Furthermore, some pioneering studies have elucidated that efficient tumor hypoxia attenuation or tumor acidity neutralization could also improve the abscopal effect of RT by reversing tumor immunosuppression to more efficiently reject metastatic tumors. − However, the impact of tumor glucose metabolism modulation on the therapeutic potency of RT has been relatively less studied.…”

“…It has been reported that biocompatible calcium carbonate (CaCO 3 )-based nanomaterials could be used as the core materials to fabricate pH-responsive nanotheranostics for improved cancer diagnosis and treatment. , They are also able to neutralize the tumor acidity by reacting with protons to improve the therapeutic potency of RT and other cancer treatments. ,, Considering that the impacts of simultaneous modulation of tumor hypoxia and acidity on tumor treatments has been rarely reported, we herein designed a fluorinated CaCO 3 loaded with PFC to function as tumor-acidity-responsive oxygen nanoshuttles. In the present study, we first synthesized a dopamine-grafted perfluorosebacic acid (DA 2 -PFSEA) as the organic ligand to coat amorphous CaCO 3 in the presence of ferric ions (Fe 3+ ) via the surface-protected etching method.…”

Connecting Calcium-Based Nanomaterials and Cancer: From Diagnosis to Therapy

“…Moreover, the inherent non-toxic and biocompatibility of Ca-NMs facilitate their applications in tumor diagnosis and treatment [ 30 ]. Therefore, Ca-NMs, such as calcium phosphate (CaP) [ 31 ], calcium carbonate (CaCO 3 ) [ 32 – 34 ], and hydroxyapatite (HAp) [ 35 , 36 ], are an attractive class of inorganic calcium-based materials because of their degradation products native presence in the human environment. In addition, calcium peroxide (CaO 2 ) is also included in this functional calcium-based material due to its powerful anti-tumor properties.…”

Construction of a novel radiosensitivity- and ferroptosis-associated gene signature for prognosis prediction in gliomas

“…Zou et al revealed that T cells could promote ferroptosis in tumor cells, thus providing a potential therapeutic approach 11 . Feng et al reported that reprogramming the immunosuppressive metabolic microenvironment could improve the curative effect of radiotherapy in breast cancer 50 . In this study, the functional enrichment analysis and KEGG pathway analysis revealed that immune cells and immune-related pathways were highly enriched in glioma-related biological processes.…”