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Transcription Factor Networks Drive Tumor Progression and Immune Microenvironment Remodeling in Hepatocellular Carcinoma
by
, ,
Sang Hoon Lee
1,†, 
Ju Won Ahn
2,†,
Wonbin Choi
3,†,
Jina Kim
4,
Joon Yeon Hwang
5,
Jae-Hwan Kim
3,
Hyaekang Kim
6,* and
Woori Kwak
2,* 1
Department of Digital Health, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul 06355, Republic of Korea
2
Department of Medical and Biological Sciences, The Catholic University of Korea, Bucheon 14662, Republic of Korea
3
Department of Biomedical Science, College of Life Science, CHA University, Seongnam 13488, Republic of Korea
4
Department of Biotechnology, The Catholic University of Korea, Bucheon 14662, Republic of Korea
5
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul 06355, Republic of Korea
6
Bio-Resources Bank Division, Nakdonggang National Institute of Biological Resources, Sangju 37242, Republic of Korea
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cancers 2025, 17(23), 3787; https://doi.org/10.3390/cancers17233787
Submission received: 23 October 2025
/
Revised: 18 November 2025
/
Accepted: 22 November 2025
/
Published: 26 November 2025
(This article belongs to the Section Tumor Microenvironment)
Simple Summary
Hepatocellular carcinoma (HCC) is a deadly and highly complex cancer. To better understand what makes it aggressive, we investigated the key genetic switches, known as transcription factors (TFs), that control tumor cell behavior. By analyzing vast amounts of genetic data from single cells, we identified a core network of nine TFs that drive HCC progression. We found that these TFs orchestrate a shift in tumor cells from a state of rapid growth to a more invasive and metabolically adapted state. This change also reshapes the tumor’s surroundings, creating an environment that suppresses the immune system, largely by recruiting and activating specific immune cells called SPP1+ macrophages. This coordinated action between tumor cells and immune cells promotes cancer growth and immune evasion. Our findings highlight this TF–macrophage axis as a promising new target for developing more effective HCC therapies.
Abstract
(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.
