Jiang Xiaohong, Wang Jin, Huang Weijie, Ma Haowei, Zhang Shilong, Cai Zehong, Lin Wenxin, Zheng Jintao
Department of Pharmacy, Shantou University Medical College, Shantou, 515041, China.
Prenatal Diagnosis Center, Jinan Maternal and Child Health Care Hospital, Jinan, 250001, China.
Adv Healthc Mater. 2024 Dec;13(30):e2401902. doi: 10.1002/adhm.202401902. Epub 2024 Aug 13.
Radio-immunotherapy driven by radiation-induced immunogenic cell death (ICD) is emerging as a potential opportunity to address conventional radiotherapy (RT) that is only applicable to localized tumor treatment. However, the effective activation of ICD during RT is severely limited by radiation dose, weak tumor immunogenicity, and radio-resistance caused by tumor microenvironment (TME). Herein, a novel bimetallic hybrid nanoscale coordination nanostimulator is first proposed by phosphate backbone doped with copper ions (Cu) and hafnium ions (Hf), and then modified with polyvinylpyrrolidone (PVP). The PVPylated Cu/Hf-doped phosphate nanostimulator (denoted as CHP) exhibits effective reprogramming of TME, including depletion of tumor endogenous glutathione (GSH), relief of tumor hypoxia and repolarization of M2 phenotypic macrophages, thus achieving tumor radiosensitization at low X-ray irradiation dose, gradually accumulation of tumor endogenous reactive oxygen species (ROS) and augmenting cuproptosis. In addition, cuproptosis can amplify RT-induced anti-tumor immunity through ICD activation, ultimately resulting in a robust anti-tumor immune response and long-term immunity, evidenced by distant tumor growth inhibition of 4T1-tumor-bearing models. More interestingly, it is discovered that CHP-mediated cuproptosis can be intensifiable during X-ray irradiation. Taken together, this work presents a novel radio-cuproptosis-immunotherapy cascade strategy, offering a new perspective for innovation in the treatment field of breast cancer.
由辐射诱导的免疫原性细胞死亡（ICD）驱动的放射免疫疗法正在成为一种潜在的机会，以解决仅适用于局部肿瘤治疗的传统放射疗法（RT）。然而，放疗期间ICD的有效激活受到辐射剂量、肿瘤免疫原性弱以及肿瘤微环境（TME）引起的放射抗性的严重限制。在此，首次提出了一种新型双金属杂化纳米级配位纳米刺激器，它由掺杂铜离子（Cu）和铪离子（Hf）的磷酸骨架组成，然后用聚乙烯吡咯烷酮（PVP）进行修饰。经PVP修饰的Cu/Hf掺杂磷酸纳米刺激器（称为CHP）表现出对TME的有效重编程，包括消耗肿瘤内源性谷胱甘肽（GSH）、缓解肿瘤缺氧以及使M2表型巨噬细胞重新极化，从而在低X射线照射剂量下实现肿瘤放射增敏，使肿瘤内源性活性氧（ROS）逐渐积累并增强铜死亡。此外，铜死亡可通过激活ICD放大放疗诱导的抗肿瘤免疫，最终导致强大的抗肿瘤免疫反应和长期免疫，4T1荷瘤模型的远处肿瘤生长抑制证明了这一点。更有趣的是，发现CHP介导的铜死亡在X射线照射期间可增强。综上所述，这项工作提出了一种新型的放射-铜死亡-免疫治疗级联策略，为乳腺癌治疗领域的创新提供了新的视角。
