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<p>Tumor immunotherapy is often compromised by an immunosuppressive tumor microenvironment (TME) characterized by abnormal vasculature and exhausted T cells. Here, given the role of nitric oxide (NO) in favorably remodeling the TME, we engineered <i>Escherichia coli</i> Nissle 1917 (ECN) with a synthetic arginine–NO circuit (ECN-NO) that modifies the arginine synthesis pathway to constitutively synthesize arginine and enable sustained NO production. Specifically, deletion of the arginine repressor ArgR relieved feedback inhibition of arginine biosynthesis, whereas co-expression of argininosuccinate synthase and lyase (ArgG/ArgH), together with <i>Bacillus subtilis</i> nitric oxide synthase (BsNOS), enabled sustained NO production through enhanced arginine regeneration. Intratumoral colonization of ECN-NO significantly enhanced the antitumor efficacy of anti-programmed cell death ligand 1 (αPD-L1) immunotherapy, resulting in durable tumor regression across multiple solid tumor mouse models. Mechanistically, ECN-NO induced vascular normalization and dendritic cell recruitment, alleviated tumor immunosuppression and synergized with αPD-L1 to expand functional CD8<sup>+</sup> T cells, reverse T cell exhaustion and promote memory T cell formation, establishing antitumor immunity for at least 120 days.</p>

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Sustained nitric oxide production by engineered E. coli remodels the tumor microenvironment and potentiates immunotherapy

  • 期刊论文

  • 发表日期：

    2026年3月18日

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  • Shuyu Xu,
  • Tianjiao Zhang,
  • Yang Song,
  • Mengxin Wang,
  • Ruiqi Wu,
  • Mofan Li,
  • Haonan Wang,
  • Xinxin Xie,
  • Qingfeng Chen,
  • Xiaotu Ma,
  • Xiaolong Liang

摘要

Tumor immunotherapy is often compromised by an immunosuppressive tumor microenvironment (TME) characterized by abnormal vasculature and exhausted T cells. Here, given the role of nitric oxide (NO) in favorably remodeling the TME, we engineered Escherichia coli Nissle 1917 (ECN) with a synthetic arginine–NO circuit (ECN-NO) that modifies the arginine synthesis pathway to constitutively synthesize arginine and enable sustained NO production. Specifically, deletion of the arginine repressor ArgR relieved feedback inhibition of arginine biosynthesis, whereas co-expression of argininosuccinate synthase and lyase (ArgG/ArgH), together with Bacillus subtilis nitric oxide synthase (BsNOS), enabled sustained NO production through enhanced arginine regeneration. Intratumoral colonization of ECN-NO significantly enhanced the antitumor efficacy of anti-programmed cell death ligand 1 (αPD-L1) immunotherapy, resulting in durable tumor regression across multiple solid tumor mouse models. Mechanistically, ECN-NO induced vascular normalization and dendritic cell recruitment, alleviated tumor immunosuppression and synergized with αPD-L1 to expand functional CD8+ T cells, reverse T cell exhaustion and promote memory T cell formation, establishing antitumor immunity for at least 120 days.