Molecular mechanisms, current therapeutics, and emerging strategies in esophageal cancer: A comprehensive review

Esophageal cancer (EC) is a prevalent and highly aggressive malignancy with an increasing global burden that is associated with significant mortality. The principal histological subtypes of EC, esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), exhibit distinct etiological factors and genomic landscapes. This review systematically categorizes and synthesizes findings from key EC clinical trials conducted over the past five years. Specifically, we integrate the current understanding of molecular pathogenesis, targeted therapeutic approaches, the tumor immune microenvironment, and emerging treatment strategies. Immunotherapy has emerged as a breakthrough in the management of EC; however, the progress in the development of targeted therapies has been notably slower. To address this gap, promising future directions in targeted therapy may include tyrosine kinase inhibitors (TKIs), cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, agents targeting the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway, and epigenetic modulators. Despite these significant therapeutic advances, EC remains a highly lethal disease, which underlines the critical and ongoing need to identify novel therapeutic vulnerabilities and explore innovative combination treatment regimens.