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

作者：Tian-Ci Wang, Yupu Xu, Zhengfeng Zhang, Yaqi Wu, Long Chen, Xiaodong Zheng, Xiaodong Zheng, Hui Peng, Qiang Zou, Rui Sun, Hongdi Ma, Haoyu Sun, Zhigang Tian, Xiaohu Zheng, Xiaohu Zheng · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-64296-z · 被引用次数：5 · 研究领域：Immune cells in cancer、Immune Cell Function and Interaction、Single-cell and spatial transcriptomics

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. Interleukin-2 (IL-2) and checkpoint inhibitors such as anti-TIGIT have been used individually as tumour therapies. Here the authors fuse IL-2 and anti-TIGIT in a combined therapeutic and show that this promotes Treg cell fragility in the tumour environment which in turn promotes neutrophil function to enhance CD8 T cell anti-tumour function in mouse models.