Work

E2F1 signatures stratify immunotherapy response and reveal YWHAQ vulnerability in esophageal squamous cell carcinoma

Year: 2026

Type: article

Abstract: To improve biological interpretation of immune checkpoint inhibitor (ICI) response in esophageal squamous cell carcinoma (ESCC), we developed an E2F1 transcriptional regulation-related framework integrating spatial multi-omics and experimental validation. Single-cell and post-treatment spatial analyses localized E2F1-associated activity predominantly to malignant epithelial states. In ten ESCC Xenium specimens, paired patient-level analyses linked E2F1-high epithelial neighborhoods to lower CD8 effector T-cell and B-cell densities, a lower immune-active niche score, and higher epithelial CD274 -positive fractions. In harmonized public ICI cohorts, E2F1 .Sig functioned as an exploratory response-stratification signature, achieving the highest mean area under the curve (AUC) among evaluated immune signatures across validation and external testing cohorts. Separately, TCGA analyses supported prognostic associations of a 20-gene Hub- E2F1 .Sig risk score. In ESCC, Hub- E2F1 .Sig-based subtyping defined three immune microenvironmental states with distinct survival patterns. Cluster1 showed a more favorable immune contexture and better prognosis, suggesting its association with immune responsiveness. YWHAQ , a key Hub- E2F1 .Sig gene, was associated with poor prognosis, and YWHAQ depletion reduced malignant phenotypes, increased cisplatin-associated apoptosis, and attenuated PD-1/PD-L1-associated immunosuppressive features in vitro and in vivo. Virtual screening identified 6’-Sialyllactose as an in silico candidate YWHAQ-binding compound. These findings support an exploratory E2F1-centered framework and nominate YWHAQ as an ESCC-focused therapeutic hypothesis.

Source: npj Precision Oncology

DOI: 10.1038/s41698-026-01773-8