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Here, we generated MNK1 knockout cancer cell lines, resulting in diminished CSC properties in vitro and slowed tumor growth in vivo. Using a multiomics approach, we functionally demonstrated that loss of MNK1 restricts tumor cell metabolic adaptation by reducing glycolysis and increasing dependence on oxidative phosphorylation. Furthermore, MNK1-null breast and pancreatic tumor cells demonstrated suppressed metastasis to the liver, but not the lung. Analysis of The Cancer Genome Atlas (TCGA) data from breast cancer patients validated the positive correlation between MNK1 and glycolytic enzyme protein expression. This study defines metabolic perturbations as a previously unknown consequence of targeting MNK1\/2, which may be therapeutically exploited.<\/jats:p>","DOI":"10.1126\/sciadv.adi7673","type":"journal-article","created":{"date-parts":[[2024,9,13]],"date-time":"2024-09-13T17:59:31Z","timestamp":1726250371000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":6,"title":["Blocking tumor-intrinsic MNK1 kinase restricts metabolic adaptation and diminishes liver metastasis"],"prefix":"10.1126","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2618-8326","authenticated-orcid":true,"given":"Samuel E. 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