Epithelial-mesenchymal transition (EMT) contributes to high tumor heterogeneity and the immunosuppressive environment of the HCC tumor microenvironment (TME). Here, we developed EMT-related genes phenotyping clusters and systematically evaluated their impact on HCC prognosis, the TME, and drug efficacy prediction. We identified HCC specific EMT-related genes using weighted gene co-expression network analysis (WGCNA). An EMT-related genes prognostic index (EMT-RGPI) capable of effectively predicting HCC prognosis was then constructed. Consensus clustering of 12 HCC specific EMT-related hub genes uncovered two molecular clusters C1 and C2. Cluster C2 preferentially associated with unfavorable prognosis, higher stemness index (mRNAsi) value, elevated immune checkpoint expression, and immune cell infiltration. The TGF-β signaling, EMT, glycolysis, Wnt β-catenin signaling, and angiogenesis were markedly enriched in cluster C2. Moreover, cluster C2 exhibited higher TP53 and RB1 mutation rates. The TME subtypes and tumor immune dysfunction and exclusion (TIDE) score showed that cluster C1 patients responded well to immune checkpoint inhibitors (ICIs). Half-maximal inhibitory concentration (IC50) revealed that cluster C2 patients were more sensitive to chemotherapeutic and antiangiogenic agents. These findings may guide risk stratification and precision therapy for HCC patients.

上皮-间质转化 (EMT) 导致肿瘤高度异质性和 HCC 肿瘤微环境 (TME) 的免疫抑制环境。在这里，我们开发了 EMT 相关基因表型簇，并系统地评估了它们对 HCC 预后、TME 和药物疗效预测的影响。我们使用加权基因共表达网络分析 (WGCNA) 鉴定了 HCC 特异性 EMT 相关基因。然后构建了能够有效预测HCC预后的EMT相关基因预后指数（EMT-RGPI）。12 个 HCC 特异性 EMT 相关中枢基因的共识聚类揭示了两个分子簇 C1 和 C2。Cluster C2 优先与不良预后、较高的干性指数 (mRNAsi) 值、升高的免疫检查点表达和免疫细胞浸润相关。TGF-β 信号、EMT、糖酵解、Wnt β-连环蛋白信号和血管生成在簇 C2 中显着丰富。此外，簇 C2 表现出更高的 TP53 和 RB1 突变率。TME 亚型和肿瘤免疫功能障碍和排除 (TIDE) 评分显示，C1 组患者对免疫检查点抑制剂 (ICI) 反应良好。半数最大抑制浓度 (IC50) 显示 C2 组患者对化疗和抗血管生成剂更敏感。这些发现可能指导 HCC 患者的风险分层和精准治疗。半数最大抑制浓度 (IC50) 显示 C2 组患者对化疗和抗血管生成剂更敏感。这些发现可能指导 HCC 患者的风险分层和精准治疗。半数最大抑制浓度 (IC50) 显示 C2 组患者对化疗和抗血管生成剂更敏感。这些发现可能指导 HCC 患者的风险分层和精准治疗。