Esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype of esophageal cancer, accounting for approximately 90% of cases worldwide, with a particularly high incidence in Asian populations. ESCC is characterized by aggressive behavior and pronounced tumor heterogeneity. Although surgical resection remains the primary curative treatment, patients with locally advanced disease frequently experience recurrence and distant metastasis, resulting in poor clinical outcomes. Therefore, there is an urgent need to deepen our understanding of ESCC at the molecular level to facilitate precision diagnosis and treatment.
In recent years, high-throughput omics technologies and integrative multi-omics analyses have provided powerful tools for systematically elucidating key molecular alterations, regulatory networks, and potential therapeutic targets in ESCC. This study integrates recent advances in omics technologies in the ESCC field and highlights their important contributions to the identification of diagnostic biomarkers, prognostic indicators, and therapeutic targets.
Key findings from the study include:
1. Key signaling pathways and molecular feathers: the RTK/RAS, PI3K/AKT, cell cycle, TNF, TP53, Wnt, and Notch signaling pathways play central roles in ESCC tumorigenesis. Moreover, several molecules, such as TP53, NOTCH1, PIK3CA, FGFR, SOX2, PAX9, and SIM2 have been identified as key molecular factors in ESCC.
2. Identified diagnostic biomarkers, prognostic biomarkers, and therapeutic targets: Genomic profiling has revealed actionable alterations such as PIK3CA, FGFR1, and SOX2 amplifications, providing new opportunities for precision therapy. Epigenomic and transcriptomic analyses have identified DNA methylation–based early detection markers (e.g., PAX9 and SIM2) and immune-related transcriptomic subtypes associated with prognosis and responsiveness to immunotherapy. Proteomic and metabolomic studies have further uncovered activation of cell cycle and spliceosome related pathways, as well as altered lactate metabolism, offering additional insights into biomarkers and therapeutic vulnerabilities.
3. Translational potential of multi-omics in ESCC: Multi-omics approaches elucidate tumor heterogeneity, molecular subtypes, and tumor microenvironmental features, dissect key oncogenic signaling mechanisms, and enable the identification of diagnostic and prognostic biomarkers. In addition, multi-omics support precision oncology by guiding patient stratification and informing the discovery of actionable therapeutic targets, thereby bridging molecular insights with clinical applications in ESCC.
Despite these advances, multi-omics studies that have substantially improved our understanding of ESCC carcinogenesis often rely on high-cost platforms such as whole-genome sequencing, single-cell sequencing, and spatial omics technologies. Their routine clinical implementation remains limited by challenges including lack of standardized workflows, insufficient bioinformatics capacity, and inadequate multicenter validation, resulting in a persistent gap between research discoveries and clinical application. Future efforts should focus on translating key findings into low-cost, robust, and standardized diagnostic assays, improving automated analytical pipelines, validating molecular classifications and biomarkers in prospective clinical trials, and integrating artificial intelligence to further advance precision diagnosis and treatment in ESCC.
DOI:10.1093/procel/pwag005