alphaTIGIT-guided IL-15 mimetics enable potent and safe antitumor immunity

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.