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<p>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.</p> Graphical Abstract <p></p>

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Metal-organic framework nanoparticles activate cGAS-STING pathway to improve radiotherapy sensitivity

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年2月21日

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  • Xinyao Hu,
  • Hua Zhu,
  • Yang Shen,
  • Lang Rao,
  • Jiayi Li,
  • Xiaoqin He,
  • Ximing Xu

摘要

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.

Graphical Abstract