Uridine depletion impairs CD8⁺ T cell antitumor activity through N-glycosylation

Immune checkpoint blockade (ICB) faces limitations owing to high cost and restricted efficacy. This study identifies SNX17 as a key mediator of ICB resistance. Elevated SNX17 correlates with poor anti-PD-1 response in humans and mice. SNX17 deletion in tumor cells inhibits tumor growth via CD8 + T cell-dependent mechanisms. SNX17 reduces uridine in the tumor microenvironment (TME), suppressing IFN-γ and upregulating PD1 in CD8 + T cells. Exogenous uridine shows antitumor efficacy comparable to anti-PD-1/PD-L1 in low-SNX17 tumors and overcomes resistance in high-SNX17 models. Uridine enhances CD8 + T cell function by promoting CD45 N-glycosylation and LCK phosphorylation. Mechanistically, SNX17 stabilizes RUNX2, promoting UPP1 transcription and uridine degradation in the TME. These findings position SNX17 as an ICB response biomarker and nominate uridine as a cost-effective immunotherapeutic strategy. • Uridine boosts CD8+ T cell antitumor and overcomes ICB resistance in high-SNX17 tumors • The SNX17-RUNX2-UPP1 axis modulates uridine levels within the TME • Uridine augments the antitumor function of CD8+ T cells by promoting CD45 N-glycosylation • High SNX17 and UPP1 predict poor anti-PD-1 response and survival in CRC patients Xiao et al. reveal that sorting nexin 17 (SNX17) promotes the synthesis of uridine phosphorylase 1 (UPP1) in tumor cells, leading to a decrease in uridine concentration within the tumor microenvironment (TME). This reduction subsequently impairs the antitumor efficacy of CD8⁺ T cells in the TME.