Comprehensive Pan‐Cancer Analysis of ABCA1: Insights From Multi‐Omics Data and Exploratory Validation in Esophageal Squamous Cell Carcinoma

ABSTRACT

Cancer remains a major cause of global mortality, necessitating the identification of novel biomarkers to improve prognosis and guide therapy. ABCA1, an ATP‐binding cassette transporter involved in cholesterol efflux, has been implicated in tumorigenesis, yet its pan‐cancer roles and clinical relevance are not fully understood. We conducted a comprehensive multi‐omics analysis of ABCA1 across diverse cancers, evaluating its expression, prognostic significance, genomic alterations, tumor immune microenvironment interactions, and regulatory mechanisms. ABCA1 expression was dysregulated in multiple malignancies and associated with poor prognosis in STAD, STES, and LGG, though favorable outcomes were observed in KIRC. It correlated with genomic instability markers (TMB, MSI, HRD), immune cell infiltration, and cancer stemness. Pathway analyses revealed enrichment in cholesterol metabolism and efferocytosis‐related pathways. Among the cancer types examined, esophageal squamous cell carcinoma (ESCC) was selected for exploratory functional validation due to its prognostic relevance. In vitro, ABCA1 knockdown inhibited proliferation, invasion, and migration in ESCC cell lines. In silico drug sensitivity analysis suggested potential associations with dasatinib response and panobinostat resistance, warranting further experimental validation. Collectively, these findings highlight the context‐dependent associations of ABCA1 with cancer progression, immune modulation, and genomic integrity, suggesting its potential utility as a prognostic biomarker that warrants further investigation for therapeutic targeting.