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
  • 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. [email protected].
  • 7. Department of Urology, Nanjing Drum Tower Hospital, State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu, China. [email protected].
  • 8. Department of Urology, Nanjing Drum Tower Hospital, State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu, China. [email protected].
  • 9. Jiangsu Key Laboratory of Molecular Medicine, Division of Anatomy and Histo-embryology, Medical School, Nanjing University, Nanjing, Jiangsu, China. [email protected].
  • # 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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