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<p>Non-nucleotide stimulators of interferon gene (STING) agonists hold promise as immunotherapeutic agents for postsurgical adjuvant treatment of tumors. However, their limited effect duration hampers therapeutic effectiveness, necessitating prolonged administration of multiple doses that heightens infection risk and impacts patient compliance. Here, we develop an implantable dual-drug depot in a sandwich-like configuration, with a non-nucleotide STING agonist (MSA-2) in the outer layers of 3D-printed scaffolds and an immunogenic apoptosis inducer (doxorubicin, DOX) in the inner layer of electrospun fibers. We discover that MSA-2 can elicit endoplasmic reticulum stress-mediated and general immunogenic apoptosis of cancer cells. The stimulations with tumor-associated antigens and damage-associated molecular patterns from cancer cells, along with proinflammatory factors secreted by matured dendritic cells and M1-polarized macrophages, can depolymerize intracellular microtubules guiding activated STING trafficking towards lysosomes for degradation. Collectively, the dual-drug depots can initiate a long-lasting cascaded immunotherapy and chemotherapy, suppressing postsurgical tumor recurrence and metastasis.</p>

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Cascaded immunotherapy with implantable dual-drug depots sequentially releasing STING agonists and apoptosis inducers

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月14日

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  • Kai Li,
  • Xuan Yu,
  • Yanteng Xu,
  • Haixia Wang,
  • Zheng Liu,
  • Chong Wu,
  • Xing Luo,
  • Jiancheng Xu,
  • Youqiang Fang,
  • Enguo Ju,
  • Shixian Lv,
  • Hon Fai Chan,
  • Yeh-Hsing Lao,
  • Weiling He,
  • Yu Tao,
  • Mingqiang Li

摘要

Non-nucleotide stimulators of interferon gene (STING) agonists hold promise as immunotherapeutic agents for postsurgical adjuvant treatment of tumors. However, their limited effect duration hampers therapeutic effectiveness, necessitating prolonged administration of multiple doses that heightens infection risk and impacts patient compliance. Here, we develop an implantable dual-drug depot in a sandwich-like configuration, with a non-nucleotide STING agonist (MSA-2) in the outer layers of 3D-printed scaffolds and an immunogenic apoptosis inducer (doxorubicin, DOX) in the inner layer of electrospun fibers. We discover that MSA-2 can elicit endoplasmic reticulum stress-mediated and general immunogenic apoptosis of cancer cells. The stimulations with tumor-associated antigens and damage-associated molecular patterns from cancer cells, along with proinflammatory factors secreted by matured dendritic cells and M1-polarized macrophages, can depolymerize intracellular microtubules guiding activated STING trafficking towards lysosomes for degradation. Collectively, the dual-drug depots can initiate a long-lasting cascaded immunotherapy and chemotherapy, suppressing postsurgical tumor recurrence and metastasis.