Abstract

Radiotherapy remains a cornerstone in the management of oesophageal cancer, yet resistance to radiation significantly compromises treatment outcomes. This review aims to explore the intrinsic and extrinsic biological mechanisms underlying radiotherapy resistance in oesophageal squamous cell carcinoma (OSCC) and oesophageal adenocarcinoma (OAC), with a focus on translational and therapeutic implications. A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science to identify peer-reviewed studies up to 2024 that investigated molecular and microenvironmental factors contributing to radioresistance in oesophageal cancer. Both preclinical and clinical studies were included. Data were synthesized and categorized based on cellular mechanisms and tumour microenvironmental influences. Key intrinsic mechanisms of resistance include the dysregulation of microRNAs (e.g., miR-31, miR-330-5p), TP53 mutations affecting DNA repair and apoptosis, and overactivation of the PI3K/AKT/mTOR signalling pathway. Extrinsic factors such as tumour hypoxia, pro-inflammatory cytokines (e.g., IL-6), immune cell evasion, and poor CD8+ T-cell infiltration further reduce radiosensitivity. Emerging strategies such as pathway-specific inhibitors, hypoxia-activated prodrugs, gene therapies, and miRNA modulation show promise in reversing these resistance mechanisms. Radiotherapy resistance in oesophageal cancer arises from complex interactions between tumour-intrinsic genetic alterations and extrinsic microenvironmental factors. Understanding these mechanisms is critical for developing personalized, resistance-targeted therapies. Future clinical approaches should integrate molecular profiling and immunologic context to overcome therapeutic resistance and improve patient outcomes.