αTIGIT-IL2 achieves tumor regression by promoting tumor-infiltrating regulatory T cell fragility in mouse models
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.
Authors
- Rui Sun (ORCID: https://orcid.org/0000-0001-5259-9391)
- Hongdi Ma (ORCID: https://orcid.org/0000-0002-1381-1772)
- Xiaohu Zheng (ORCID: https://orcid.org/0000-0002-6957-6329)
- Zhigang Tian (ORCID: https://orcid.org/0000-0002-5512-6378)
- Qiang Zou (ORCID: https://orcid.org/0000-0002-1362-2007)
- Long Chen (ORCID: https://orcid.org/0000-0002-2979-5033)
- Xiaodong Zheng (ORCID: https://orcid.org/0000-0002-9684-6400)
- Haoyu Sun (ORCID: https://orcid.org/0000-0002-7506-8806)
- Zhengfeng Zhang (ORCID: https://orcid.org/0000-0003-1856-9126)
- Hui Peng
- Yupu Xu (ORCID: https://orcid.org/0000-0002-6060-1268)
- Yaqi Wu (ORCID: https://orcid.org/0009-0006-6651-310X)
- Tian-Ci Wang
Institutions
- University of Science and Technology of China (CN)
- Shanghai Medical College of Fudan University (CN)
- Hefei University of Technology (CN)
- Fudan University (CN)
- Hefei University (CN)
- Fudan University Shanghai Cancer Center (CN)
- Tongren Hospital (CN)
- Shanghai Cancer Institute (CN)
- Shenzhen Institutes of Advanced Technology (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-10-17
- DOI
- https://doi.org/10.1038/s41467-025-64296-z
- Citations
- 2
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 1.59
Funders
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- Natural Science Foundation of Anhui Province
- National Key Research and Development Program of China
- Fundamental Research Funds for the Central Universities