甲胎蛋白（AFP）由类干细胞和预后不良的肝细胞癌瘤细胞表达，是一种临床肿瘤生物标志物。AFP已被证明能抑制树突状细胞分化和成熟，以及阻断氧化磷酸化。在此，我们采用了两种最近开发的单细胞分析方法scMEP（单细胞代谢分析）和SCENITH（单细胞能量代谢通过剖析翻译抑制），以鉴定导致人树突状细胞功能抑制的关键代谢途径。来自肿瘤的AFP显著增加了树突状细胞的糖酵解能力和葡萄糖依赖性，而来自正常脐血的AFP没有这种效应，从而导致了葡萄糖摄取和乳酸分泌的增加。特别是电子传递链中的关键分子受肿瘤来源的AFP调控。这些代谢变化发生在mRNA和蛋白质水平上，对树突状细胞的刺激能力产生了负面影响。肿瘤来源的AFP明显比脐血来源的AFP结合更多的多不饱和脂肪酸。多不饱和脂肪酸结合AFP增加了代谢偏差并促进树突状细胞功能抑制。在体外，多不饱和脂肪酸抑制树突状细胞分化，而ω-6多不饱和脂肪酸与肿瘤来源的AFP结合后具有强大的免疫调节作用。这些发现提供了关于AFP如何对抗先天免疫反应以限制抗肿瘤免疫力的机制性见解。

Alpha-fetoprotein (AFP) is expressed by stem-like and poor outcome hepatocellular cancer tumors and is a clinical tumor biomarker. AFP has been demonstrated to inhibit dendritic cell differentiation and maturation and to block oxidative phosphorylation. To identify the critical metabolic pathways leading to human dendritic cell functional suppression, here we utilized two recently described single cell profiling methods, scMEP (single-cell metabolic profiling) and SCENITH (single-cell energetic metabolism by profiling translation inhibition). Glycolytic capacity and glucose dependence of dendritic cells was significantly increased by tumor-derived, but not normal cord blood-derived, AFP, leading to increased glucose uptake and lactate secretion. Key molecules in the electron transport chain in particular were regulated by tumor-derived AFP. These metabolic changes occurred at mRNA and protein levels, with negative impact on dendritic cell stimulatory capacity. Tumor-derived AFP bound significantly more polyunsaturated fatty acids than cord blood-derived AFP. Polyunsaturated fatty acids bound to AFP increased metabolic skewing and promoted dendritic cell functional suppression. Polyunsaturated fatty acids inhibited dendritic cell differentiation in vitro, and ω-6 polyunsaturated fatty acids conferred potent immunoregulation when bound to tumor-derived AFP. Together, these findings provide mechanistic insights into how AFP antagonizes the innate immune response to limit anti-tumor immunity.