Jing Ding,1,* Xia Zou,1,* Xuefeng Huang,1,2 Le Yu,1 Huangming Hong,1 Tongyu Lin1 

1Department of Medical Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, Sichuan, People’s Republic of China; 2Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Tongyu Lin, Department of Medical Oncology, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, People’s Republic of China, Tel +86-28-85420656, Email linty@sysucc.org.cn

Background: Hepatocellular carcinoma (HCC) is a prevalent lethal cancer that remains challenging to treat. Therefore, investigation of novel targets and therapeutic strategies is essential. The role of ZBED4 in cancer remains unclear.
Methods: Data were sourced from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), International Cancer Genome Consortium (ICGC), and Genomics of Drug Sensitivity in Cancer (GDSC) databases. Various web platforms and R software, have been utilized. Multiplex immunofluorescence was performed on a human HCC tissue microarray.
Results: High ZBED4 expression correlates with poor prognosis and immune cell infiltration in multiple cancers. ZBED4 is potentially involved in the regulation of the tumor environment by T cells, with a focus on CD8⁺ T cells. In HCC, tissues with elevated ZBED4 expression exhibit a higher prevalence of Tregs and neutrophils, whereas those with reduced ZBED4 expression show an increased abundance of CD8⁺ T cells, activated CD4⁺ T cells, gamma/delta T cells, and activated natural killer (NK) cells. Elevated ZBED4 expression in HCC patients is associated with a reduced response to immune checkpoint blockade but an improved response to chemotherapy and most targeted therapies. A multi-gene prognostic signature has been developed and confirmed across various HCC cohorts. Multiplex immunofluorescence study demonstrated that ZBED4 was linked to poor prognosis and negatively correlated with CD8⁺ T cell infiltration.
Conclusion: Our research elucidates the role of ZBED4, its strong link to immune infiltration, and its potential as a prognostic and therapeutic biomarker for HCC.
Plain Language Summary: Why was this study done?
Hepatocellular carcinoma (HCC) is a common and aggressive liver cancer with limited treatment options. The ZBED gene family plays roles in cancer progression, but the function of one member, ZBED4, was unknown. This study explored whether ZBED4 could serve as a biomarker to predict patient outcomes or guide therapies for HCC.
What did the researchers do?
We analyzed data from public cancer databases and patient tissue samples to investigate ZBED4’s role in HCC. We examined:How ZBED4 levels vary in tumors compared to normal tissues.Whether ZBED4 affects immune cells in the tumor environment.Its link to patient survival and response to treatments like chemotherapy and immunotherapy.
What did we find?High ZBED4 levels were linked to worse survival and advanced cancer stages.Tumors with more ZBED4 had fewer cancer-fighting immune cells (like CD8⁺ T cells) and more immunosuppressive cells (like Tregs).ZBED4 may predict drug sensitivity: patients with high ZBED4 responded better to chemotherapy but poorly to immunotherapy.A 10-gene signature based on ZBED4-related genes helped identify high-risk HCC patients.
What do these results mean?
ZBED4 could be a useful biomarker to guide treatment decisions in HCC. Targeting ZBED4 might improve outcomes, though further research is needed to confirm this. Future basic and clinical studies should explore whether combining ZBED4-targeted therapies with immune-boosting treatments could enhance their effectiveness.
Key terms explained:Biomarker: A measurable indicator of disease or treatment response.Immunotherapy: Treatments that help the immune system fight cancer.Tumor microenvironment (TME): The surrounding cells and molecules that influence tumor growth.
This work opens new avenues of ZBED4 for personalized HCC therapy and highlights its importance in the tumor microenvironment and cancer progression.

Keywords: ZBED4, pan-cancer, hepatocellular carcinoma, immune infiltration, therapy, prognosis