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The mechanism of this resistance remains unclear. RNA sequencing from cetuximab\u2010sensitive and \u2010resistant specimens revealed an activation of the tryptophan pathway and elevation of IDO1 and IDO2 in cetuximab\u2010resistant CRC patients. In\u00a0vitro, in\u00a0vivo, and clinical specimens confirmed the upregulation of IDO1and IDO2 and the Kyn\/Trp after cetuximab treatment. Additionally, the IDO inhibitor, epacadostat, could effectively inhibit the migration and proliferation of cetuximab\u2010resistant CRC cells while promoting apoptosis. Compared to epacadostat monotherapy, the combination of cetuximab and epacadostat showed a stronger synergistic anti\u2010tumor effect. Furthermore, in\u00a0vivo experiments confirmed that combination therapy effectively suppressed tumor growth. Mechanistically, KEGG pathway analysis revealed the activation of the IFN\u2010\u03b3 pathway in cetuximab\u2010resistant CRC tissues. Luciferase reporter assays confirmed the transcriptional activity of IDO1 following cetuximab treatment. Silencing IFN\u2010\u03b3 then suppressed the upregulation induced by cetuximab. Moreover, we observed that the combination reduced the concentration of the tryptophan metabolite kynurenine, promoted the infiltration of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T lymphocytes, and enhanced the polarization of M1 macrophages within the tumor microenvironment, thereby exerting potent anti\u2010tumor immune effects. Overall, our results confirm the remarkable therapeutic efficacy of combining cetuximab with epacadostat in cetuximab\u2010resistant CRC. Our findings may provide a novel target for overcoming cetuximab resistance in CRC.\n                  <\/jats:p>","DOI":"10.1111\/cas.70057","type":"journal-article","created":{"date-parts":[[2025,3,19]],"date-time":"2025-03-19T00:49:56Z","timestamp":1742345396000},"page":"1715-1729","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Epacadostat Overcomes Cetuximab Resistance in Colorectal Cancer by Targeting\n                    <scp>IDO<\/scp>\n                    \u2010Mediated Tryptophan Metabolism"],"prefix":"10.1111","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-3562-1773","authenticated-orcid":false,"given":"Yimin","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Gastroenterology Zhongshan Hospital, Fudan University  Shanghai 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