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.