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Colorectal cancer (CRC) is one of the most common malignant tumors in the digestive system. Immune checkpoint blockade (ICB) is a promising strategy for CRC treatment, but its limited efficacy poses a challenge. Bioinformatics methods were used to screen ferroptosis-related genes in CRC. Cellular biology methods investigated endothelial PAS domain protein 1 (EPAS1) impact on cellular characteristics, stemness, and ferroptosis. Finally, in vivo experiments validated EPAS1's influence on anti-PD-1 therapy efficacy. We have found that EPAS1 is a risk gene in CRC, which can inhibit the growth, invasion, and stemness of colon cancer cells both in vitro and in vivo, and promote ferroptosis. Mechanistically, caveolin 1 (CAV1) regulates the expression of von Hippel-Lindau tumor suppressor (VHL) to inhibit the ubiquitination of EPAS1, increase its stability, further enhance the expression of nuclear receptor coactivator 4 (NCOA4) and autophagy-lysosome formation, leading to cell iron overload and inducing ferroptosis. Our study confirms EPAS1 regulates ferroptosis, impacting epithelial-mesenchymal transition (EMT) and stemness in CRC cells, and highlights its role in ICB. These findings inform CRC treatment.