Defective N-glycosylation in tumor-infiltrating CD8+ T cells impairs IFN-?-mediated effector function

T cell-mediated antitumor immunity is modulated, in part, by N-glycosylation. However, the interplay between N-glycosylation and the loss of effector function in exhausted T cells has not yet been fully investigated. Here, we delineated the impact of N-glycosylation on the exhaustion of tumor-infiltrating lymphocytes in a murine colon adenocarcinoma model, focusing on the IFN-?-mediated immune response. We found that exhausted CD8(+) T cells downregulated the oligosaccharyltransferase complex, which is indispensable for N-glycan transfer. Concordant N-glycosylation deficiency in tumor-infiltrating lymphocytes leads to loss of antitumor immunity. Complementing the oligosaccharyltransferase complex restored IFN-? production and alleviated CD8(+) T cell exhaustion, resulting in reduced tumor growth. Thus, aberrant glycosylation induced in the tumor microenvironment incapacitates effector CD8(+) T cells. Our findings provide insights into CD8(+) T cell exhaustion by incorporating N-glycosylation to understand the characteristic loss of IFN-?, opening new opportunities to amend the glycosylation status in cancer immunotherapies.