Long-term accumulation of adenosine (Ado) in tumor tissues helps to establish the immunosuppressive tumor microenvironment and to promote tumor development. Regulation of Ado metabolism is particularly pivotal for blocking Ado-mediated immunosuppression. The activity of adenosine kinase (ADK) for catalyzing the phosphorylation of Ado plays an essential role in regulating Ado metabolism. Specifically, accumulated Ado in the tumor microenvironment occupies the active site of ADK, inhibiting the phosphorylation of Ado. Phosphate can protect ADK from inactivation and restore the activity of ADK. Herein, calcium phosphate-reinforced iron-based metal-organic frameworks (CaP@Fe-MOFs) are designed to reduce Ado accumulation and to inhibit Ado-mediated immunosuppressive response in the tumor microenvironment. CaP@Fe-MOFs are found to regulate the Ado metabolism by promoting ADK-mediated phosphorylation and relieving the hypoxic tumor microenvironment. Moreover, CaP@Fe-MOFs can enhance the antitumor immune response via Ado regulation, including the increase of T lymphocytes and dendritic cells and the decrease of regulatory T lymphocytes. Finally, CaP@Fe-MOFs are used for cancer treatment in mice, alleviating the Ado-mediated immunosuppressive response and achieving tumor suppression. This study may offer a general strategy for blocking the Ado-mediated immunosuppression in the tumor microenvironment and further for enhancing the immunotherapy efficacy in vivo.

中文翻译：

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磷酸钙增强金属有机框架调节腺苷介导的免疫抑制

腺苷（Ado）在肿瘤组织中的长期积累有助于建立免疫抑制性肿瘤微环境，促进肿瘤的发展。Ado 代谢的调节对于阻断 Ado 介导的免疫抑制尤为关键。腺苷激酶（ADK）催化Ado磷酸化的活性在调节Ado代谢中起重要作用。具体而言，肿瘤微环境中积累的Ado占据了ADK的活性位点，抑制了Ado的磷酸化。磷酸盐可以保护ADK免于失活并恢复ADK的活性。在此，磷酸钙增强的铁基金属有机框架（CaP@Fe-MOFs）旨在减少 Ado 的积累并抑制 Ado 介导的肿瘤微环境中的免疫抑制反应。发现 CaP@Fe-MOFs 通过促进 ADK 介导的磷酸化和缓解缺氧的肿瘤微环境来调节 Ado 代谢。此外，CaP@Fe-MOFs可以通过Ado调节增强抗肿瘤免疫反应，包括增加T淋巴细胞和树突状细胞，减少调节性T淋巴细胞。最后，CaP@Fe-MOFs 用于小鼠的癌症治疗，减轻 Ado 介导的免疫抑制反应并实现肿瘤抑制。该研究可能为阻断 Ado 介导的肿瘤微环境中的免疫抑制提供一般策略，并进一步增强体内免疫治疗的功效。包括T淋巴细胞和树突状细胞的增加和调节性T淋巴细胞的减少。最后，CaP@Fe-MOFs 用于小鼠的癌症治疗，减轻 Ado 介导的免疫抑制反应并实现肿瘤抑制。该研究可能为阻断 Ado 介导的肿瘤微环境中的免疫抑制提供一般策略，并进一步增强体内免疫治疗的功效。包括T淋巴细胞和树突状细胞的增加和调节性T淋巴细胞的减少。最后，CaP@Fe-MOFs 用于小鼠的癌症治疗，减轻 Ado 介导的免疫抑制反应并实现肿瘤抑制。该研究可能为阻断 Ado 介导的肿瘤微环境中的免疫抑制提供一般策略，并进一步增强体内免疫治疗的功效。