(1) Background: Hepatocellular carcinoma (HCC) remains a major cause of cancer mortality and is characterized by pronounced inter- and intra-tumoral heterogeneity and therapy resistance. We aimed to define core transcriptional circuits that drive HCC malignancy and to delineate how these programs shape the tumor microenvironment (TME). (2) Methods: We integrated single-cell, spatial, and bulk transcriptomic datasets from public cohorts. (3) Results: We identified nine tumor-restricted transcription factors (TFs)—HTATIP2, HES6, ILF2, E2F1, MYBL2, DDIT3, FOXM1, HMGA1, and ETV4—whose expression and regulon activity associated with malignant phenotypes and poor survival. These TFs organize a progression axis from an early proliferative state (cluster C4) toward an invasive, metabolically adapted state (cluster C1) enriched for hypoxia, epithelial–mesenchymal transition (EMT), and inflammatory signaling. The C1 state remodeled the TME by establishing an immunosuppressive niche marked by expansion of T regulatory cells (Treg) and by accumulation of SPP1+macrophages. These macrophages, recruited and polarized by C1 tumor cells, exhibited M2-like, pro-angiogenic, and immunosuppressive features and engaged epithelial, immune, and stromal partners via SPP1-CD44 and SPP1-integrin interactions. (4) Conclusions: In summary, a tumor-intrinsic TF network cooperates with SPP1+macrophage signaling to promote a permissive microenvironment and HCC progression. This integrated axis highlights tractable vulnerabilities for therapeutic intervention.
（1）背景：肝细胞癌（HCC）仍是癌症死亡的主要原因，其显著特征包括明显的肿瘤间及肿瘤内异质性以及治疗抵抗性。本研究旨在明确驱动HCC恶性进展的核心转录调控环路，并阐明这些程序如何塑造肿瘤微环境（TME）。（2）方法：我们整合了来自公共队列的单细胞转录组、空间转录组及批量转录组数据集。（3）结果：我们鉴定出九个肿瘤限制性转录因子（TFs）——HTATIP2、HES6、ILF2、E2F1、MYBL2、DDIT3、FOXM1、HMGA1和ETV4，其表达及调控子活性与恶性表型及不良预后相关。这些转录因子构建了一个从早期增殖状态（C4亚群）向侵袭性、代谢适应状态（C1亚群）演进的进展轴，该C1状态富集缺氧、上皮-间质转化（EMT）及炎症信号通路。C1状态通过形成以调节性T细胞（Treg）扩增和SPP1+巨噬细胞聚集为特征的免疫抑制生态位，重塑了肿瘤微环境。这些由C1肿瘤细胞招募并极化的巨噬细胞表现出M2样、促血管生成及免疫抑制特性，并通过SPP1-CD44和SPP1-整合素相互作用与上皮细胞、免疫细胞及基质细胞建立联系。（4）结论：综上所述，肿瘤内在的转录因子网络与SPP1+巨噬细胞信号协同作用，共同营造了促癌微环境并推动HCC进展。这一整合轴为治疗干预揭示了可操作的潜在靶点。
肿瘤(癌症)患者之家