UFL1 ablation in T cells suppresses PD-1 UFMylation to enhance anti-tumor immunity

UFMylation is an emerging ubiquitin-like post -translational modification that regulates various biological processes. Dysregulation of the UFMylation pathway leads to human diseases, including cancers. However, the physiological role of UFMylation in T cells remains unclear. Here, we report that mice with conditional knockout (cKO) Ufl1 , a UFMylation E3 ligase, in T cells exhibit effective tumor control. Single -cell RNA sequencing analysis shows that tumor -infiltrating cytotoxic CD8 + T cells are increased in Ufl1 cKO mice. Mechanistically, UFL1 promotes PD -1 UFMylation to antagonize PD -1 ubiquitination and degradation. Furthermore, AMPK phosphorylates UFL1 at Thr536, disrupting PD -1 UFMylation to trigger its degradation. Of note, UFL1 ablation in T cells reduces PD -1 UFMylation, subsequently destabilizing PD -1 and enhancing CD8 + T cell activation. Thus, Ufl1 cKO mice bearing tumors have a better response to anti-CTLA-4 immunotherapy. Collectively, our findings uncover a crucial role of UFMylation in T cells and highlight UFL1 as a potential target for cancer treatment.