Hu Xinyao, Zhu Hua, Shen Yang, Rao Lang, Li Jiayi, He Xiaoqin, Xu Ximing
Cancer Center, Renmin Hospital of Wuhan University, NO. 99 Zhang Zhidong Road, Wuchang District, Wuhan, 430060, China.
Institute of Chemical Biology, Shenzhen Bay Laboratory, Shenzhen, 518132, China.
J Nanobiotechnology. 2025 Feb 21;23(1):131. doi: 10.1186/s12951-025-03229-w.
Tumor immunotherapy aims to harness the immune system to identify and eliminate cancer cells. However, its full potential is hindered by the immunosuppressive nature of tumors. Radiotherapy remains a key treatment modality for local tumor control and immunomodulation within the tumor microenvironment. Yet, the efficacy of radiotherapy is often limited by tumor radiosensitivity, and traditional radiosensitizers have shown limited effectiveness in hepatocellular carcinoma (HCC). To address these challenges, we developed a novel multifunctional nanoparticle system, ZIF-8@MnCO@DOX (ZMD), designed to enhance drug delivery to tumor tissues. In the tumor microenvironment, Zn²⁺ and Mn²⁺ ions released from ZMD participate in a Fenton-like reaction, generating reactive oxygen species (ROS) that promote tumor cell death and improve radiosensitivity. Additionally, the release of doxorubicin (DOX)-an anthracycline chemotherapeutic agent-induces DNA damage and apoptosis in cancer cells. The combined action of metal ions and double-stranded DNA (dsDNA) from damaged tumor cells synergistically activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, thereby initiating a robust anti-tumor immune response. Both in vitro and in vivo experiments demonstrated that ZMD effectively activates the cGAS-STING pathway, promotes anti-tumor immune responses, and exerts a potent tumor-killing effect in combination with radiotherapy, leading to regression of both primary tumors and distant metastases. Our work provides a straightforward, safe, and effective strategy for combining immunotherapy with radiotherapy to treat advanced cancer.
肿瘤免疫疗法旨在利用免疫系统来识别和消除癌细胞。然而，肿瘤的免疫抑制特性阻碍了其全部潜力的发挥。放射疗法仍然是局部肿瘤控制和肿瘤微环境免疫调节的关键治疗方式。然而，放射疗法的疗效常常受到肿瘤放射敏感性的限制，并且传统的放射增敏剂在肝细胞癌（HCC）中显示出有限的效果。为了应对这些挑战，我们开发了一种新型多功能纳米颗粒系统，即ZIF-8@MnCO@DOX（ZMD），旨在增强药物向肿瘤组织的递送。在肿瘤微环境中，从ZMD释放的Zn²⁺和Mn²⁺离子参与类Fenton反应，产生活性氧（ROS），促进肿瘤细胞死亡并提高放射敏感性。此外，阿霉素（DOX）——一种蒽环类化疗药物——的释放诱导癌细胞中的DNA损伤和凋亡。来自受损肿瘤细胞的金属离子和双链DNA（dsDNA）的联合作用协同激活环磷酸鸟苷-腺苷酸合成酶（cGAS）-干扰素基因刺激物（STING）途径，从而引发强大的抗肿瘤免疫反应。体外和体内实验均表明，ZMD有效地激活cGAS-STING途径，促进抗肿瘤免疫反应，并与放射疗法联合发挥强大的肿瘤杀伤作用，导致原发性肿瘤和远处转移灶均消退。我们的工作为将免疫疗法与放射疗法联合用于治疗晚期癌症提供了一种直接、安全且有效的策略。
