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

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.