低蛋白饮食通过增强自然杀伤细胞功能限制肝脏黑色素瘤转移

Liver metastasis represents a major clinical challenge across multiple cancer types, contributing significantly to patient morbidity and mortality due to the liver's unique immunometabolic environment that supports tumour growth. Low-protein diet (LPD) has been shown to reshape the immunological landscape of the liver and provide a protective phenotype against inflammation and infection. Here, we investigate the impact of LPD on the progression of metastatic melanoma. C57BL/6 female mice were fed ad libitum with an isocaloric control diet (22% protein) or with LPD (6% protein) for a duration of two or six weeks before experimental endpoints. Mice were injected with B16F10 melanoma cells intravenously two weeks before experimental endpoints. Nuclear magnetic resonance was used for the detection of metabolites in the liver, lungs and blood serum. Transcriptome analysis was performed on mRNA sequencing data obtained from lung and liver RNA. Flow cytometry was used to screen immune cell populations in the liver. LPD-fed mice showed an 87.5% reduction in melanoma metastatic modules in the liver ( p = 0.021, Mann-Whitney U (MWU) test), while no reduction was observed in the lungs. Metabolite analysis in the liver identified 15 differentially abundant metabolites ( p.adj < 0.05, MWU test) and pathway impact analysis (False Discovery Rate (FDR) < 0.05) with MetaboAnalyst identified 14 enriched pathways between the control diet and LPD. Tryptophan catabolism was down-regulated by LPD. Transcriptome analysis in the liver with DESeq2 identified 240 significantly upregulated and 244 downregulated genes in LPD (|log2FC| > 1 and p.adj < 0.05, Wald test). Gene-set enrichment analysis identified several pathways deregulated in LPD, including downregulation of Tryptophan metabolism, which confirmed our metabolite analysis. These results indicate a shift in immune cell function in the liver, with the Kynurenine pathway heavily impacted. We therefore examined liver immune cells by flow cytometry. Isolated immune cells from the liver showed a 25.2% ( p.adj = 0.012, MWU test) increase in the Natural Killer (NK) cell (CD45 + , CD3 - , NK1.1 + ) population between the control diet and LPD mice. These results suggest an immunological shift toward enhanced NK cell activity in the livers of LPD mice, potentially driven by reduced Tryptophan metabolism and consequently lower downstream Kynurenine levels. Because Kynurenine can result in downregulation of genes encoding NK-activating receptors, its reduction may help sustain NK cell activation. This heightened NK activity could contribute to the decreased number of metastatic melanoma nodules observed in LPD mice. Future work will focus on elucidating the mechanisms underlying this NK cell-mediated protective effect.