Transcription Factor Networks Drive Tumor Progression and Immune Microenvironment Remodeling in Hepatocellular Carcinoma

(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.