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<p><i>PRCC-TFE3</i> 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 (<i>NMRK2</i>), which is transcriptionally upregulated by PRCC-TFE3 fusion protein, as a pivotal molecule in the energy metabolism remodeling of <i>PRCC-TFE3</i> rRCC. However, the molecular mechanism by which NMRK2-mediated enhancement of nicotinamide adenine dinucleotide (NAD<sup>+</sup>) synthesis contributes to tumor progression in <i>PRCC-TFE3</i> 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<sup>+</sup>T cells, leading to the emergence of immune-ignorant phenotypes in <i>PRCC-TFE3</i> rRCC. Furthermore, it was shown that the increased NAD<sup>+</sup> metabolism driven by NMRK2 enhanced the stability of CD38 protein through SIRT1-mediated deacetylation, which underlines impairment of CD8<sup>+</sup>T cells and the development of an immunosuppressive state in <i>PRCC-TFE3</i> rRCC. Our findings not only elucidated a mechanism underlying immunological ignorance in <i>PRCC-TFE3</i> rRCC but also propose potential therapeutic targets.</p>

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

  • 期刊论文

  • 发表日期：

    2025年9月17日

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  • Yi Chen,
  • Xuwentai Liu,
  • Mengmeng Wu,
  • Xiang Dong,
  • Wenliang Ma,
  • Fan Feng,
  • Yibing Ding,
  • Ping Dong,
  • Weidong Ding,
  • Luqing Zhang,
  • Ning Liu,
  • Weidong Gan,
  • Dongmei Li

摘要

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.