2. Academic Validation
  3. NMRK2 leads to the depletion of CD8+T cells by mediating the enhancement of NAD+-SIRT1-CD38 axis in PRCC-TFE3 rRCC

NMRK2 leads to the depletion of CD8+T cells by mediating the enhancement of NAD+-SIRT1-CD38 axis in PRCC-TFE3 rRCC

  • Oncogene. 2025 Sep 17. doi: 10.1038/s41388-025-03577-9.
Yi Chen # 1 2,  Xuwentai Liu # 1 3,  Mengmeng Wu 3,  Xiang Dong 1,  Wenliang Ma 4,  Fan Feng 1,  Yibing Ding 5,  Ping Dong 3,  Weidong Ding 3,  Luqing Zhang 3,  Ning Liu 6,  Weidong Gan 7,  Dongmei Li 8 9
Affiliations

Affiliations

  • 1 Department of Urology, Nanjing Drum Tower Hospital, State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu, China.
  • 2 Department of Cardiology, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
  • 3 Jiangsu Key Laboratory of Molecular Medicine, Division of Anatomy and Histo-embryology, Medical School, Nanjing University, Nanjing, Jiangsu, China.
  • 4 Department of Thoracic Surgery, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, Jiangsu, China.
  • 5 Translational Medicine Core Facilities, Medical School, Nanjing University, Nanjing, Jiangsu, China.
  • 6 Department of Urology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China. LNnjubg@163.com.
  • 7 Department of Urology, Nanjing Drum Tower Hospital, State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu, China. gwd@nju.edu.cn.
  • 8 Department of Urology, Nanjing Drum Tower Hospital, State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu, China. lidm@nju.edu.cn.
  • 9 Jiangsu Key Laboratory of Molecular Medicine, Division of Anatomy and Histo-embryology, Medical School, Nanjing University, Nanjing, Jiangsu, China. lidm@nju.edu.cn.
  • # Contributed equally.
PMID: 40962858 DOI: 10.1038/s41388-025-03577-9
Abstract

PRCC-TFE3 rearrangement renal cell carcinoma (rRCC) is an independent subtype of rRCC caused by chromosomal translocation and rearrangement. Previous studies have revealed that nicotinamide riboside kinase 2 (NMRK2), which is transcriptionally upregulated by PRCC-TFE3 fusion protein, as a pivotal molecule in the energy metabolism remodeling of PRCC-TFE3 rRCC. However, the molecular mechanism by which NMRK2-mediated enhancement of nicotinamide adenine dinucleotide (NAD+) synthesis contributes to tumor progression in PRCC-TFE3 rRCC remains unclear. In this study, utilizing immune system-humanized mice model and in vitro cell models, we demonstrated that elevated expression of NMRK2 impaired the cytotoxic functions of CD8+T cells, leading to the emergence of immune-ignorant phenotypes in PRCC-TFE3 rRCC. Furthermore, it was shown that the increased NAD+ metabolism driven by NMRK2 enhanced the stability of CD38 protein through SIRT1-mediated deacetylation, which underlines impairment of CD8+T cells and the development of an immunosuppressive state in PRCC-TFE3 rRCC. Our findings not only elucidated a mechanism underlying immunological ignorance in PRCC-TFE3 rRCC but also propose potential therapeutic targets.

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