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

Tianci Wang, Yupu Xu, Zhengfeng Zhang, Yaqi Wu, Long Chen, Xiaodong Zheng, Hui Peng, Qiang Zou, Rui Sun, Hongdi Ma (), Haoyu Sun (), Zhigang Tian () and Xiaohu Zheng ()
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Tianci Wang: University of Science and Technology of China
Yupu Xu: University of Science and Technology of China
Zhengfeng Zhang: University of Science and Technology of China
Yaqi Wu: University of Science and Technology of China
Long Chen: University of Science and Technology of China
Xiaodong Zheng: University of Science and Technology of China
Hui Peng: University of Science and Technology of China
Qiang Zou: Shanghai Jiao Tong University School of Medicine
Rui Sun: University of Science and Technology of China
Hongdi Ma: University of Science and Technology of China
Haoyu Sun: Hefei TG ImmunoPharma Corporation Limited
Zhigang Tian: University of Science and Technology of China
Xiaohu Zheng: University of Science and Technology of China

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-64296-z

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