2. Academic Validation
  3. Uridine depletion impairs CD8⁺ T cell antitumor activity through N-glycosylation

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

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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