The Immunological and Prognostic Landscape of TFAP4 in Cancer: A Single-Cell RNA Sequencing Perspective

Linghui Zhong; Zidong Feng; Feng Li; Honghui Zhao; Ziyu Zhang; Wenyang Zhang; Heiko Hermeking; Lei Shi

doi:10.1016/j.abb.2025.110551

The Immunological and Prognostic Landscape of TFAP4 in Cancer: A Single-Cell RNA Sequencing Perspective

Arch Biochem Biophys. 2025 Jul 11:110551. doi: 10.1016/j.abb.2025.110551. Online ahead of print.

Authors

Linghui Zhong¹, Zidong Feng¹, Feng Li¹, Honghui Zhao¹, Ziyu Zhang¹, Wenyang Zhang¹, Heiko Hermeking², Lei Shi³

Affiliations

¹ RNA Oncology Group, School of Public Health, Lanzhou University, Lanzhou, People's Republic of China, 730000.
² Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University, Thalkirchner Strasse 36, 80337, Munich, Germany. Electronic address: heiko.hermeking@med.uni-muenchen.de.
³ RNA Oncology Group, School of Public Health, Lanzhou University, Lanzhou, People's Republic of China, 730000. Electronic address: leishi@lzu.edu.cn.

PMID: 40653182
DOI: 10.1016/j.abb.2025.110551

Abstract

Transcription factor activating enhancer-binding protein 4 (TFAP4) has been implicated in tumorigenesis, yet its precise role in the tumor microenvironment remains inadequately characterized. In this study, we employed single-cell RNA sequencing and multi-omics analysis to investigate the immunological and prognostic significance of TFAP4 across various cancer types. Our analysis reveals that TFAP4 is upregulated in malignant epithelial cells across multiple cancer types and correlated with advanced tumor stages and poor patient survival. High TFAP4 expression is associated with activation of oncogenic signaling pathways, including MAPK, JAK-STAT, and TGF-β signalling. TFAP4-high expressing tumors exhibit reduced CD8⁺ and CD4⁺ T cell infiltration and increased T cell exhaustion. Cell-cell communication analysis reveals that TFAP4-high cells orchestrate immunosuppressive signaling in the tumor microenvironment. Notably, TFAP4 knockdown enhances the efficacy of chemotherapy and is downregulated following anti-PD-1 treatment, indicating its role in modulating therapeutic response. Collectively, our findings provide novel insights into the immunological functions of TFAP4, highlighting its potential as a prognostic biomarker and therapeutic target in cancer.

Keywords: TFAP4; biomarker; chemotherapy sensitization; immune exhaustion; single-cell RNA-seq.