In this discussion, researchers Jun Zhang, Lanlan Zhou, Shuai Zhao, and Wafik S. El-Deiry delve into innovative approaches for tackling refractory metastatic gastrointestinal cancers. They unveil exciting findings on the synergistic effects of the FDA-approved drugs TAS102 and regorafenib. Their research suggests this combination could improve survival rates and combat cancer stemness. With promising preclinical results, they emphasize the need for further clinical studies to validate these advances in cancer treatment.