Targeting a disintegrin and metalloprotease (ADAM) 17-CD122 axis enhances CD8⁺ T cell effector differentiation and anti-tumor immunity

CD8⁺ T cell immune responses are regulated by multi-layer networks, while the post-translational regulation remains largely unknown. Transmembrane ectodomain shedding is an important post-translational process orchestrating receptor expression and signal transduction through proteolytic cleavage of membrane proteins. Here, by targeting the sheddase A Disintegrin and Metalloprotease (ADAM)17, we defined a post-translational regulatory mechanism mediated by the ectodomain shedding in CD8⁺ T cells. Transcriptomic and proteomic analysis revealed the involvement of post-translational regulation in CD8⁺ T cells. T cell-specific deletion of ADAM17 led to a dramatic increase in effector CD8⁺ T cell differentiation and enhanced cytolytic effects to eliminate pathogens and tumors. Mechanistically, ADAM17 regulated CD8⁺ T cells through cleavage of membrane CD122. ADAM17 inhibition led to elevated CD122 expression and enhanced response to IL-2 and IL-15 stimulation in both mouse and human CD8⁺ T cells. Intriguingly, inhibition of ADAM17 in CD8⁺ T cells improved the efficacy of chimeric antigen receptor (CAR) T cells in solid tumors. Our findings reveal a critical post-translational regulation in CD8⁺ T cells, providing a potential therapeutic strategy of targeting ADAM17 for effective anti-tumor immunity.