Effect of MINK1 deficiency on gene expression in CD8+ OT-I TILs

The accumulation of ROS in the tumor microenvironment is a major driving factor for immunosuppression. While its detrimental effects on T cell activation are recognized, the precise molecular mechanisms remain unclear. In this study, we identify MINK1 as a ROS-responsive kinase in regulating CD8+ T cell-mediated anti-tumor immunity. We found that MINK1 ablation enhances the effector function of intratumoral CD8⁺ T cells by facilitate CD8+ effector T-cell differentiation, thereby enabling sustained tumor control. Mechanistically, MINK1 interacts with LATS1 and activates the Hippo pathway, thereby suppressing cytotoxic gene expression and inhibiting CD8+ T cell differentiation into effector subtypes. Finally, we proved that targeting MINK1 in both CAR-T and TCR-T cells could improve anti-tumor CD8+ T cell response in solid tumor models. Pharmacological inhibition of MINK1 also enhances anti-tumor immune responses in mice. Thus, this work uncovered MINK1 as a pivotal driver for CD8+ T cell dysfunction in tumors and highlights its potential as a therapeutic target for enhancing cancer immunotherapy.