Esophageal cancer: from pathogenesis to precision therapies

Esophageal cancer (EC), encompassing primarily esophageal squamous-cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), continues to pose a significant global health burden, which is largely due to delayed diagnosis and limited therapeutic efficacy. In this review, we synthesize current insights into key aspects of EC, including established risk factors, the stepwise process of tumorigenesis, strategies for early detection and prevention, and emerging therapeutic approaches. Emphasis is particularly placed on the molecular underpinnings of (1) early tumor initiation and malignant progression, with a focus on genetic mutations, epigenetic modifications, and alterations within the tumor microenvironment; (2) the clonal expansion and metabolic reprogramming that play essential roles in shaping the evolutionary trajectory of esophageal cancer, thereby promoting intratumoral heterogeneity; (3) the transition from normal epithelium to invasive carcinoma in both ESCC and EAC driven by sequential disruptions of molecular networks governing epithelial homeostasis; and (4) advances in early screening techniques and minimally invasive interventions that may offer new opportunities for EC prevention and early detection, especially in high-risk populations. In addition, we summarize recent progress in precision treatment, including chemotherapy, targeted therapy, immunotherapy, and multidisciplinary treatment. By delineating the molecular and cellular mechanisms underlying EC initiation and progression, this review aims to inform future directions in early diagnosis, risk stratification, and individualized therapy, ultimately contributing to improved clinical outcomes and precision prevention of EC.