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_reg 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_reg cells and promotes their fragility in the tumor milieu. These fragile-like T_reg 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 T_reg cells and promote their fragility in the tumor milieu, resulting in robust antitumor immunity.