Molecular Mechanisms of Chemoradiotherapy Resistance in Esophageal Cancer and Clinical Response Strategies: From the Tumor Microenvironment to Precision Medicine

Esophageal squamous cell carcinoma (ESCC) is the sixth leading cause of cancer-related deaths globally, with more than half of cases occurring in China. Although chemoradiotherapy (CRT) is a major treatment modality for ESCC, its efficacy is often limited by tumor resistance. The 5-year survival rate of esophageal cancer patients is less than 30%, and the prognosis is poor. The mechanisms of induced resistance in cancer mainly include multi-dimensional factors such as the regulation of the tumor microenvironment (TME), the metabolic reprogramming of cancer-associated fibroblasts (CAFs), and the imbalanced proliferation of cancer stem cells. New strategies are urgently needed to break through this bottleneck. The study primarily focuses on reviewing the regulation of the tumor microenvironment, abnormal drug metabolism and transport, epigenetic modifications, and signaling pathways, aiming to reveal the mechanisms of CRT resistance, summarize strategies to overcome CRT resistance, and explore new treatment strategies such as targeted therapy and immunotherapy combination. This review emphasize the importance of multidisciplinary collaboration and individualized treatment to improve the cure rate and survival of ESCC patients.