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<p>The efficacy of antitumor immunotherapy is closely associated with the expansion of tumor-infiltrating CD8<sup>+</sup> T cells. However, within the tumor microenvironment, CD8<sup>+</sup> T cells often exhibit reduced proliferation due to persistent exposure to tumor antigens. The cytokine IL-2 is a potent growth factor that can drive the expansion of tumor-infiltrating lymphocytes. While its clinical application has been severely limited by systemic toxicity and in vivo instability. To address these challenges, we have developed a dual-responsive system (EcN<sub>IL-2</sub>@UCNP/Gel-CTX) leveraging the hypoxic tropisms of <i>E. coli</i> Nissle 1917(EcN). This system is capable of producing IL-2 in situ upon near-infrared (NIR) irradiation and releasing low-dose cyclophosphamide (CTX) in response to matrix metalloproteinase-2 (MMP-2) in the tumor microenvironment. The EcN<sub>IL-2</sub>@UCNP/Gel-CTX system not only drives the expansion of CD8<sup>+</sup> T cells and boost the activity of NK cells but also reduces Treg cell populations, thereby remodeling the immune microenvironment and eliciting robust tumor-specific immune responses in H22 subcutaneous tumors in mice and confers long-term protection against tumor rechallenge by promoting the generation of durable memory T cells. Our findings provide an both light and tumor microenvironment responsive platform for enhanced cancer immunotherapy.</p> Graphical Abstract <p></p>

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Improving T cell expansion by optogenetically engineered bacteria-loaded MMP-2-responsive cyclophosphamide for antitumor immunotherapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月28日

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  • Jiawen Chen,
  • Renjiang Kong,
  • Yuzhi Qiu,
  • Sihan Chen,
  • Yidi Liu,
  • Xi Yu,
  • Xiangliang Yang,
  • Yan Zhang,
  • Yanhong Zhu

摘要

The efficacy of antitumor immunotherapy is closely associated with the expansion of tumor-infiltrating CD8+ T cells. However, within the tumor microenvironment, CD8+ T cells often exhibit reduced proliferation due to persistent exposure to tumor antigens. The cytokine IL-2 is a potent growth factor that can drive the expansion of tumor-infiltrating lymphocytes. While its clinical application has been severely limited by systemic toxicity and in vivo instability. To address these challenges, we have developed a dual-responsive system (EcNIL-2@UCNP/Gel-CTX) leveraging the hypoxic tropisms of E. coli Nissle 1917(EcN). This system is capable of producing IL-2 in situ upon near-infrared (NIR) irradiation and releasing low-dose cyclophosphamide (CTX) in response to matrix metalloproteinase-2 (MMP-2) in the tumor microenvironment. The EcNIL-2@UCNP/Gel-CTX system not only drives the expansion of CD8+ T cells and boost the activity of NK cells but also reduces Treg cell populations, thereby remodeling the immune microenvironment and eliciting robust tumor-specific immune responses in H22 subcutaneous tumors in mice and confers long-term protection against tumor rechallenge by promoting the generation of durable memory T cells. Our findings provide an both light and tumor microenvironment responsive platform for enhanced cancer immunotherapy.

Graphical Abstract