{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T01:22:23Z","timestamp":1790558543099,"version":"4.1.0"},"reference-count":130,"publisher":"American Association for Cancer Research (AACR)","issue":"11","license":[{"start":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T00:00:00Z","timestamp":1762128000000},"content-version":"vor","delay-in-days":95,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["aacrjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,11,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>Given the propensity of aggressive epithelial tumors to form hepatic metastases, we performed an in vivo cDNA screen using the mouse liver and KRASG12D\/TP53R273H pancreatic cells that identified the RNA-binding protein GCN1 as an integral component of hepatic outgrowth. RNAi experiments reveal that GCN1 triggers the integrated stress response (ISR) to activate serine, folate, and methionine biosynthetic pathways together with amino acid transporters, which act in concert to facilitate acquisition of metabolites and to restore redox homeostasis. Alongside the activation of the ISR, we found that GCN1 also functions in the nucleus where it interacts with HNRNPK to suppress the expression of MHC-I molecules and NK ligands. Intriguingly, we identified IMPACT as an endogenous competitive inhibitor of GCN1 that blocks both ISR-dependent metabolic control and disrupts HNRNPK interaction. In doing so, IMPACT enhances tumor immunogenicity to unleash NK cell killing, in addition to sensitizing metastatic tumor cells to immune checkpoint blockade.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>Metastatic tumor cells display profound immunometabolic plasticity to colonize distant organs. We identify IMPACT, an inhibitor of GCN1-stress signaling, expression of which curtailed metabolic plasticity and augmented tumor immunogenicity, sensitizing metastatic tumor cells to NK cell\u2013mediated destruction.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-24-1055","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T11:13:46Z","timestamp":1753874026000},"page":"2344-2373","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Expression of IMPACT Curtails Metabolic Plasticity and Augments NK Cell Killing to Abrogate Metastatic Growth"],"prefix":"10.1158","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7204-2248","authenticated-orcid":false,"given":"Surajit","family":"Sinha","sequence":"first","affiliation":[{"name":"1Surgical Oncology Program, NCI, National Institutes of Health, Bethesda, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8139-7016","authenticated-orcid":false,"given":"Abir Kumar","family":"Panda","sequence":"additional","affiliation":[{"name":"2Cellular Immunology Section, NIAID, National Institutes of Health, Bethesda, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6669-6002","authenticated-orcid":false,"given":"Rodrigo","family":"Xavier das Neves","sequence":"additional","affiliation":[{"name":"3Laboratory of Integrative Cancer Immunology, National Institutes of Health, Bethesda, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1641-2045","authenticated-orcid":false,"given":"Zeribe C.","family":"Nwosu","sequence":"additional","affiliation":[{"name":"4Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2628-2061","authenticated-orcid":false,"given":"Ke","family":"Xu","sequence":"additional","affiliation":[{"name":"5Department of Surgery, Brigham and Women\u2019s Hospital, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8422-3299","authenticated-orcid":false,"given":"Elke","family":"van Beek","sequence":"additional","affiliation":[{"name":"6University Medical Center Utrecht, Utrecht, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3376-3226","authenticated-orcid":false,"given":"Priyanka P.","family":"Desai","sequence":"additional","affiliation":[{"name":"1Surgical Oncology Program, NCI, National Institutes of Health, Bethesda, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2516-969X","authenticated-orcid":false,"given":"Sivasish","family":"Sindiri","sequence":"additional","affiliation":[{"name":"7Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9608-8301","authenticated-orcid":false,"given":"Sruthi","family":"Chempati","sequence":"additional","affiliation":[{"name":"2Cellular Immunology Section, NIAID, National Institutes of Health, Bethesda, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0668-4164","authenticated-orcid":false,"given":"Kirsten","family":"Remmert","sequence":"additional","affiliation":[{"name":"1Surgical Oncology Program, NCI, National Institutes of Health, Bethesda, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8061-8278","authenticated-orcid":false,"given":"Billel","family":"Gasmi","sequence":"additional","affiliation":[{"name":"7Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2684-5824","authenticated-orcid":false,"given":"Linda","family":"Bojmar","sequence":"additional","affiliation":[{"name":"8Department of Biomedical and Clinical Sciences, Linkoping University, Linkoping, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2740-3259","authenticated-orcid":false,"given":"Constantinos","family":"Zambirinis","sequence":"additional","affiliation":[{"name":"8Department of Biomedical and Clinical Sciences, Linkoping University, Linkoping, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3325-3664","authenticated-orcid":false,"given":"Alexander J.","family":"Rossi","sequence":"additional","affiliation":[{"name":"9Department of Colon and Rectal Surgery, Oschner Health, New Orleans, Louisiana."},{"name":"10Department of Surgery, Oschner Health, New Orleans, Louisiana."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6884-1047","authenticated-orcid":false,"given":"Reed I.","family":"Ayabe","sequence":"additional","affiliation":[{"name":"11Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, Complex General Surgical Oncology, University of California, Irvine, Orange, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7686-6076","authenticated-orcid":false,"given":"Michael M.","family":"Wach","sequence":"additional","affiliation":[{"name":"12Department 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