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<p>Administration of IL-2 may promote the suppressive function and proliferation of T<sub>reg</sub> cells that cause immune tolerance in patients with cancer, which causes low-dose IL-2 to fail in achieving an optimal anti-tumor effect. Here, we designed an immunocytokine by fusing IL-2 and an anti-TIGIT monoclonal antibody, named αTIGIT-IL2, that targets T<sub>reg</sub> cells and promotes their fragility in the tumor milieu. These fragile-like T<sub>reg</sub> cells show impaired suppressive function and high IFN-γ production, triggering an immune-reactive tumor microenvironment. Such inflammation leads to the recruitment and functional reprogramming of intratumoral neutrophils, improving cross-talk between neutrophils and CD8<sup>+</sup> T cells and enhancing the antitumor ability of CD8<sup>+</sup> T cells. Combination therapy with αTIGIT-IL2 and PD-1 blocker could eliminate triple-negative breast cancer (TNBC) tumors resistant to immune checkpoint blockade (ICB) therapy. These findings provide the basis for developing a new generation of immunocytokines that target T<sub>reg</sub> cells and promote their fragility in the tumor milieu, resulting in robust antitumor immunity.</p>

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αTIGIT-IL2 achieves tumor regression by promoting tumor-infiltrating regulatory T cell fragility in mouse models

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月17日

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  • Tianci Wang,
  • Yupu Xu,
  • Zhengfeng Zhang,
  • Yaqi Wu,
  • Long Chen,
  • Xiaodong Zheng,
  • Hui Peng,
  • Qiang Zou,
  • Rui Sun,
  • Hongdi Ma,
  • Haoyu Sun,
  • Zhigang Tian,
  • Xiaohu Zheng

摘要

Administration of IL-2 may promote the suppressive function and proliferation of Treg cells that cause immune tolerance in patients with cancer, which causes low-dose IL-2 to fail in achieving an optimal anti-tumor effect. Here, we designed an immunocytokine by fusing IL-2 and an anti-TIGIT monoclonal antibody, named αTIGIT-IL2, that targets Treg cells and promotes their fragility in the tumor milieu. These fragile-like Treg cells show impaired suppressive function and high IFN-γ production, triggering an immune-reactive tumor microenvironment. Such inflammation leads to the recruitment and functional reprogramming of intratumoral neutrophils, improving cross-talk between neutrophils and CD8+ T cells and enhancing the antitumor ability of CD8+ T cells. Combination therapy with αTIGIT-IL2 and PD-1 blocker could eliminate triple-negative breast cancer (TNBC) tumors resistant to immune checkpoint blockade (ICB) therapy. These findings provide the basis for developing a new generation of immunocytokines that target Treg cells and promote their fragility in the tumor milieu, resulting in robust antitumor immunity.