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<p>The response rate of oncolytic microbe-triggered cancer immunotherapies are commonly restricted by in vivo dose-dependent toxicity. To address the limitation, we exploited the selective growth advantage conferred by tetrathionate respiration in inflamed tissue to engineer <i>Salmonella Typhimurium (S. Typhimurium)</i> VNP20009 into a self-amplifying oncolytic system with enhanced antitumor efficacy. The hydrogen sulfide (H<sub>2</sub>S) donor-anchored, biocompatible lipids-encapsulated VNP20009 exhibits good intratumoral enrichment after intravenous administration in tumor-bearing mice. In the inflammatory tumor microenvironment, H<sub>2</sub>S released from the donor can be oxidized to tetrathionate, which promotes the proliferation of VNP20009, leading to a marked increase compared to the bare VNP20009. This self-reinforced reproduction augments the activation of microbe-mediated immunogenic pyroptosis in the tumor, thereby triggering a significant immunotherapeutic effect in orthotopic breast tumor-bearing and melanoma-bearing mouse models. This study offers a potential strategy for developing high-effectiveness and low-side effect oncolytic microbe biotherapeutics in cancer treatment.</p>

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Enhanced self-proliferated oncolytic microbial system aided by tetrathionate respiration for potentiated immunotherapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月18日

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  • Yuxuan Yu,
  • Zhichao Chen,
  • Ximing Zhang,
  • Yinglei Zhai,
  • Mengchi Sun,
  • Jin Sun

摘要

The response rate of oncolytic microbe-triggered cancer immunotherapies are commonly restricted by in vivo dose-dependent toxicity. To address the limitation, we exploited the selective growth advantage conferred by tetrathionate respiration in inflamed tissue to engineer Salmonella Typhimurium (S. Typhimurium) VNP20009 into a self-amplifying oncolytic system with enhanced antitumor efficacy. The hydrogen sulfide (H2S) donor-anchored, biocompatible lipids-encapsulated VNP20009 exhibits good intratumoral enrichment after intravenous administration in tumor-bearing mice. In the inflammatory tumor microenvironment, H2S released from the donor can be oxidized to tetrathionate, which promotes the proliferation of VNP20009, leading to a marked increase compared to the bare VNP20009. This self-reinforced reproduction augments the activation of microbe-mediated immunogenic pyroptosis in the tumor, thereby triggering a significant immunotherapeutic effect in orthotopic breast tumor-bearing and melanoma-bearing mouse models. This study offers a potential strategy for developing high-effectiveness and low-side effect oncolytic microbe biotherapeutics in cancer treatment.