Abstract 2625: αTIGIT-guided IL-15 mimetics enable potent and safe antitumor immunity.

Abstract Cytokines are powerful modulators of antitumor immunity, but their clinical use is constrained by structural instability and systemic toxicity. Although antibody-based cytokine mimetics have recently emerged to activate immune cells in vitro, their therapeutic activity in vivo remains uncertain. Here, using interleukin-15 (IL-15) as a model, we engineered bispecific antibody-based IL-15 mimetics guided by AlphaFold3-assisted structural modeling. Comparative screening of multiple formats identified tandem IL-15 mimetics with strong in vitro bioactivity, but unexpectedly showed minimal antitumor activity in vivo. Strikingly, incorporating TIGIT-directed targeting transformed these mimetics into potent and nontoxic cytokine agonists, resulting in strong tumor control associated with enhanced effector activation and expansion of intratumoral CD8+ stem-like T cells. These findings indicate that current cytokine mimetics have limited activity when used alone and require precise T-cell targeting to achieve therapeutic potency. Our study highlights a strategy to use cytokine mimetics to overcome the mismatch between immune checkpoint blockade and low-potency cis-targeted cytokines, offering a path toward safer and more effective cytokine immunotherapy. Citation Format: Xiangming Liu, Nan Li, Yang-Xin Fu, Zaopeng Yang, . αTIGIT-guided IL-15 mimetics enable potent and safe antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2625.