Wu Xirui, Zhang Junjun, Deng Zheng, Sun Xianglong, Zhang Yifan, Zhang Cai, Wang Jiadong, Yu Xinke, Yang Guangbao
State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China.
Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, Institute of Radiotherapy & Oncology, Soochow University, Suzhou 215004, China.
Biomaterials. 2025 May;316:123000. doi: 10.1016/j.biomaterials.2024.123000. Epub 2024 Dec 5.
Radiotherapy (RT) can trigger immunogenic cell death (ICD) in tumor cells and release adenosine triphosphate (ATP) to activate antitumor immunity. However, the formation of immunosuppressive adenosine (ADO) mediated by ectonucleotidases including CD39 and CD73, can exacerbate the immunosuppressive effects. Herein, a radiosensitizer-based metal-organic framework (MOF) composed of bismuth (Bi) and ellagic acid (EA) was synthesized in situ on the surface of Escherichia coli Nissle 1917 (EcN) to serve as a carrier for the CD39 inhibitor sodium polyoxotungstate (POM-1). This therapeutic platform, acting as a radiosensitizer, significantly enhances cytotoxicity against tumor cells while effectively inducing ICD and releasing high concentrations of ATP. Subsequently, the released POM-1 increases the levels of pro-inflammatory extracellular ATP while preventing tumor immunosuppression caused by the accumulation of ADO. Additionally, as a natural immune adjuvant, EcN further promotes the maturation of dendritic cells (DCs) and the infiltration of cytotoxic T lymphocytes (CTLs). As a result, such treatment initiates the destruction of established tumor growth and induces strong abscopal effects, leading to a significant inhibition of tumor metastases. This strategy presents a bacterial-based biohybrid system that facilitates RT-induced ICD while simultaneously limiting the degradation of ATP into ADO, thereby achieving sustained anti-tumor immunity.
放射疗法（RT）可触发肿瘤细胞发生免疫原性细胞死亡（ICD）并释放三磷酸腺苷（ATP）以激活抗肿瘤免疫。然而，由包括CD39和CD73在内的外切核苷酸酶介导形成的免疫抑制性腺苷（ADO）会加剧免疫抑制作用。在此，一种由铋（Bi）和鞣花酸（EA）组成的基于放射增敏剂的金属有机框架（MOF）在大肠杆菌Nissle 1917（EcN）表面原位合成，用作CD39抑制剂多氧钨酸钠（POM-1）的载体。这个治疗平台作为一种放射增敏剂，显著增强了对肿瘤细胞的细胞毒性，同时有效诱导ICD并释放高浓度的ATP。随后，释放的POM-1增加了促炎细胞外ATP的水平，同时防止了由ADO积累引起的肿瘤免疫抑制。此外，作为一种天然免疫佐剂，EcN进一步促进树突状细胞（DC）的成熟和细胞毒性T淋巴细胞（CTL）的浸润。结果，这种治疗引发了对已建立的肿瘤生长的破坏并诱导强烈的远隔效应（abscopal effect），导致肿瘤转移受到显著抑制。该策略提出了一种基于细菌的生物杂交系统，它促进RT诱导的ICD，同时限制ATP降解为ADO，从而实现持续的抗肿瘤免疫。
