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¹Department of Radiation Oncology, University of Health Sciences, Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Ankara-Türkiye DOI : 10.5505/tjo.2025.8 Gastrointestinal (GI) malignancies represent a major global health challenge, ranking among the most common cancers and leading causes of cancer-related mortality. Colorectal cancer is a principal contributor to cancer deaths, while gastric, esophageal, pancreatic, and hepatocellular carcinomas also exert a substantial burden on health care systems worldwide. Despite advances in multimodal treatment including surgery, chemotherapy, radiotherapy, and molecularly targeted agents therapeutic resistance remains a critical obstacle to durable disease control. Of particular concern are the persistently modest rates of pathological complete response following neoadjuvant chemoradiotherapy in rectal and esophageal adenocarcinomas, as well as the multifactorial resistance mechanisms observed in pancreatic cancer. These limitations highlight the urgent need to elucidate resistance biology and to develop innovative approaches that can enhance long-term outcomes. Recent research has explored radiosensitization strategies to overcome resistance. These include agents targeting DNA repair pathways, monoclonal antibodies against EGFR and VEGF signaling, immune checkpoint inhibitors, and drugs modulating tumor metabolism. Furthermore, the immunosuppressive role of the tumor immune microenvironment and cancer-associated fibroblasts has emerged as a key determinant of therapeutic response. Clinically, encouraging progress has been made: PD-1 inhibitors have achieved unexpectedly high complete response rates in rectal cancer, while the combination of radiotherapy and immunotherapy has shown significant improvements in pathological outcomes. In hepatocellular carcinoma, randomized data demonstrate a survival advantage when SBRT is combined with sorafenib compared with sorafenib alone. Collectively, current findings indicate that rational integration of radiotherapy with immunotherapy and targeted agents offers considerable promise in GI cancers, though further prospective studies are required to establish long-term survival benefits and inform clinical practice. Keywords : Gastrointestinal system cancers; immunotherapy; radiotherapy