TIGIT-targeted IL-12 fusion protein engages NK and CD8⁺ T cells for potent tumor immunotherapy

The limitation of wild-type interleukin-12 (IL-12) in its clinical application lies in its systemic activation, which results in severe toxicities. Here, we develop a fusion protein named αTIGIT-IL12 (T-12), which fuses the 13G6 (αTIGIT) antibody scFv fragment in tandem with IL-12. T-12 can selectively localize to the tumor site and concurrently target intratumoral natural killer (NK) and CD8⁺ T cells in vivo. T-12 demonstrated exceptional efficacy in reducing tumor burden across multiple tumor models in mice, dependent on NK and CD8⁺ T cells. T-12 preferentially activates tumor-infiltrating NK and CD8⁺ T cells over their peripheral counterparts, in contrast to wild-type IL-12. Compared with wild-type IL-12, T-12 exhibits greater safety upon systemic administration while treating tumor-bearing models, and the maximal tolerance dosage was elevated by up to about 100-fold. T-12 exhibits potent therapeutic efficacy in checkpoint-insensitive tumor models and metastatic tumor models. These findings underscore the potential of the T-12 fusion protein as a strategy in immunotherapy.