<b>Single-Cell Multiomics Reveals How Gut Microbiota Reprogram Hepatocellular Carcinoma Metabolism to Suppress NK Cell Surveillance Through PRDX1</b>

This study investigates the role of gut microbiota in driving immune evasion in hepatocellular carcinoma (HCC) through peroxiredoxin 1 (PRDX1)-mediated metabolic reprogramming. Using multi-omics analysis of clinical samples and experimental validation in cell and animal models, we demonstrate that HCC patients exhibit significant enrichment of Bacilli and Lactobacillales, which correlates with PRDX1 upregulation (log2FC=2.1, p<0.001) and glycolytic pathway activation. Mechanistically, Bacilli infection induces PRDX1 overexpression (4.6-fold, p<0.001), leading to increased lactate secretion (2.3-fold, p<0.01) and suppression of NK cell function through downregulation of NKG2D ligands and cytotoxicity markers (CD107a and IFN-γ reduced by 45-52%). Importantly, targeting this pathway through PRDX1 knockdown or glycolysis inhibition (2-DG) reverses these effects and restores PD-1 antibody efficacy in vivo (40% improvement, p<0.01). These findings establish for the first time a direct link between specific gut microbiota, PRDX1-driven metabolic alterations, and NK cell dysfunction in HCC, providing a mechanistic basis for novel therapeutic strategies to overcome immunotherapy resistance by modulating the microbiota-metabolism-immune axis in the tumor microenvironment.本研究探究了肠道菌群通过过氧化物还原酶1（peroxiredoxin 1, PRDX1）介导的代谢重编程，在肝细胞癌（hepatocellular carcinoma, HCC）免疫逃逸中发挥的驱动作用。本研究通过对临床样本开展多组学分析，并在细胞与动物模型中进行实验验证，证实肝细胞癌患者体内芽孢杆菌纲（Bacilli）与乳杆菌目（Lactobacillales）存在显著富集，该现象与PRDX1上调（log₂FC=2.1，P<0.001）及糖酵解通路激活呈显著相关。从机制上而言，芽孢杆菌感染可诱导PRDX1过表达（上调4.6倍，P<0.001），进而导致乳酸分泌增加（升高2.3倍，P<0.01），并通过下调NKG2D配体与细胞毒性标志物（CD107a与干扰素γ(IFN-γ)的水平分别降低45%~52%）抑制自然杀伤细胞（NK cell）的功能。值得注意的是，通过PRDX1敲低或糖酵解抑制剂2-脱氧葡萄糖（2-DG）靶向干预该通路，可逆转上述异常效应，并在体内恢复PD-1抗体（PD-1 antibody）的治疗效果（疗效提升40%，P<0.01）。本研究首次明确了特定肠道菌群、PRDX1介导的代谢改变与肝细胞癌中NK细胞功能异常三者间的直接关联，为通过调控肿瘤微环境中的菌群-代谢-免疫轴（microbiota-metabolism-immune axis）克服免疫治疗耐药提供了全新的机制基础与治疗策略方向。