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

Area of Science:

• Immunology
• Cancer Biology
• Metabolic Pathways

Background:

• Immune checkpoint blockade (ICB) therapies, while promising, face limitations in efficacy and cost.
• Identifying mechanisms of ICB resistance is crucial for improving cancer treatment outcomes.

Purpose of the Study:

• To investigate the role of SNX17 in mediating resistance to ICB.
• To explore the potential of targeting SNX17 or uridine metabolism for cancer immunotherapy.

Main Methods:

• Correlation analysis of SNX17 levels with anti-PD-1 response in human and mouse models.
• Tumor growth inhibition assays following SNX17 deletion in tumor cells.
• Assessment of uridine levels, CD8+ T cell function (IFN-γ, PD1 expression), and uridine supplementation effects.
• Mechanistic studies involving SNX17, RUNX2, UPP1, and uridine degradation.

Main Results:

• Elevated SNX17 levels correlate with poor anti-PD-1 response.
• SNX17 deletion inhibits tumor growth through CD8+ T cell-dependent mechanisms.
• SNX17 reduces tumor microenvironment uridine, suppressing T cell activity.
• Exogenous uridine demonstrates antitumor efficacy and overcomes ICB resistance, enhancing CD8+ T cell function via CD45 N-glycosylation and LCK phosphorylation.
• SNX17 stabilizes RUNX2, leading to increased uridine degradation.

Conclusions:

• SNX17 is a key mediator of ICB resistance and a potential biomarker for predicting treatment response.
• Uridine metabolism represents a novel, cost-effective immunotherapeutic target for overcoming ICB resistance and enhancing anti-tumor immunity.