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

  • Cell Metab. 2025 Dec 29:S1550-4131(25)00530-3. doi: 10.1016/j.cmet.2025.11.016.
Jianbiao Xiao  1 ,  Zhiyang Li  2 ,  Yi Ding  3 ,  Kejin Zhu  2 ,  Zhihao Zheng  3 ,  Yaowei Zhang  3 ,  Jiawen Weng  3 ,  Feifei Wang  4 ,  Yuqin Zhang  3 ,  Sisi Zeng  5 ,  Minxing Qiu  6 ,  Zhaowen Zhang  2 ,  Zhizhang Wang  7 ,  Li Liang  8
Affiliations
  • 1. Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong , China; Jinfeng Laboratory, Chongqing, China.
  • 2. Department of Pathology, Southern Medical University, Guangzhou, Guangdong, China.
  • 3. Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
  • 4. Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
  • 5. Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong , China; Jinfeng Laboratory, Chongqing, China; Department of Pathology, Southern Medical University, Guangzhou, Guangdong, China.
  • 6. Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong , China; Department of Pathology, Southern Medical University, Guangzhou, Guangdong, China.
  • 7. Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong , China; Jinfeng Laboratory, Chongqing, China. Electronic address: [email protected].
  • 8. Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong , China; Jinfeng Laboratory, Chongqing, China; Department of Pathology, Southern Medical University, Guangzhou, Guangdong, China. Electronic address: [email protected].
PMID: 41468885 DOI: 10.1016/j.cmet.2025.11.016
Abstract

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.

Keywords
CD8+ T cell; N-glycosylation; SNX17; UPP1; checkpoint blockade; immunotherapy resistance; uridine.
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