{"doi":"10.1158/2159-8290.cd-24-1055","title":"Expression of IMPACT Curtails Metabolic Plasticity and Augments NK Cell Killing to Abrogate Metastatic Growth","abstract":"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. SIGNIFICANCE: 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-mediated destruction.","journal":"Cancer Discovery","year":2025,"id":541938,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9535,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":385520,"name":"Abir K. Panda","orcid":"0000-0002-8139-7016","position":1,"is_corresponding":false},{"id":376225,"name":"Rodrigo Xavier das Neves","orcid":"0000-0001-6669-6002","position":2,"is_corresponding":false},{"id":225034,"name":"Zeribe C. Nwosu","orcid":"0000-0003-1641-2045","position":3,"is_corresponding":false},{"id":291554,"name":"Ke Xu","orcid":"0000-0003-2628-2061","position":4,"is_corresponding":false},{"id":1204673,"name":"Elke van Beek","orcid":"0009-0005-8422-3299","position":5,"is_corresponding":false},{"id":896285,"name":"Priyanka P. Desai","orcid":"0009-0002-3376-3226","position":6,"is_corresponding":false},{"id":250441,"name":"Sivasish Sindiri","orcid":"0000-0003-2516-969X","position":7,"is_corresponding":false},{"id":1407229,"name":"Sruthi Chempati","orcid":"0009-0002-9608-8301","position":8,"is_corresponding":false},{"id":434423,"name":"Kirsten Remmert","orcid":"0009-0004-0668-4164","position":9,"is_corresponding":false},{"id":225666,"name":"Billel Gasmi","orcid":"0000-0002-8061-8278","position":10,"is_corresponding":false},{"id":106388,"name":"Linda Bojmar","orcid":"0000-0002-2684-5824","position":11,"is_corresponding":false},{"id":106392,"name":"Constantinos P. Zambirinis","orcid":"0000-0003-2740-3259","position":12,"is_corresponding":false},{"id":574809,"name":"Alexander J. Rossi","orcid":"0000-0003-3325-3664","position":13,"is_corresponding":false},{"id":497201,"name":"Reed I. Ayabe","orcid":"0000-0002-6884-1047","position":14,"is_corresponding":false},{"id":381399,"name":"Michael M. Wach","orcid":"0000-0002-7686-6076","position":15,"is_corresponding":false},{"id":383858,"name":"James D. McDonald","orcid":"0000-0002-6193-4152","position":16,"is_corresponding":false},{"id":474952,"name":"Samantha M. Ruff","orcid":"0000-0001-5275-6705","position":17,"is_corresponding":false},{"id":924897,"name":"Emily A. Verbus","orcid":"0000-0001-7855-3527","position":18,"is_corresponding":false},{"id":844313,"name":"Areeba Saif","orcid":"0000-0002-6902-2254","position":19,"is_corresponding":false},{"id":1258381,"name":"Alyssa V. Eade","orcid":"0009-0009-8354-0881","position":20,"is_corresponding":false},{"id":455430,"name":"Carolina M. Larrain","orcid":"0009-0009-4773-2632","position":21,"is_corresponding":false},{"id":1430649,"name":"Lindsay R. Friedman","orcid":"0000-0002-6226-4816","position":22,"is_corresponding":false},{"id":443626,"name":"Shreya Gupta","orcid":"0000-0003-3783-0617","position":23,"is_corresponding":false},{"id":1069781,"name":"Alok Ranjan","orcid":"0009-0008-6501-7061","position":24,"is_corresponding":false},{"id":929976,"name":"Martha E. Teke","orcid":"0000-0002-6513-9543","position":25,"is_corresponding":false},{"id":352625,"name":"Tahsin M. Khan","orcid":"0000-0002-5423-1184","position":26,"is_corresponding":false},{"id":1105978,"name":"Tracey Pu","orcid":"0000-0001-7880-2183","position":27,"is_corresponding":false},{"id":929977,"name":"Amber Leila Sarvestani","orcid":"0009-0000-3795-5714","position":28,"is_corresponding":false},{"id":1430650,"name":"Carrie E. Ryan","orcid":"0009-0009-4333-1620","position":29,"is_corresponding":false},{"id":1040274,"name":"Jacob T. Lambdin","orcid":"0000-0002-3304-0557","position":30,"is_corresponding":false},{"id":1188384,"name":"Kenneth Luberice","orcid":"0000-0002-8065-8405","position":31,"is_corresponding":false},{"id":915330,"name":"Stephanie N. Gregory","orcid":"0000-0003-4242-5595","position":32,"is_corresponding":false},{"id":990695,"name":"Stephanie C. Lux","orcid":"0000-0002-3887-1077","position":33,"is_corresponding":false},{"id":971311,"name":"Hanna Hong","orcid":"0000-0001-6637-8573","position":34,"is_corresponding":false},{"id":908124,"name":"Allen J. Luna","orcid":"0009-0007-1725-7186","position":35,"is_corresponding":false},{"id":1430651,"name":"Imani A. Alexander","orcid":"0000-0002-8986-538X","position":36,"is_corresponding":false},{"id":1188385,"name":"S.R. Akmal","orcid":"0000-0003-4091-562X","position":37,"is_corresponding":false},{"id":1324580,"name":"Shahyan U. Rehman","orcid":"0000-0002-9667-3255","position":38,"is_corresponding":false},{"id":1430652,"name":"Ashley Rainey","orcid":"0009-0002-5915-0073","position":39,"is_corresponding":false},{"id":228785,"name":"Todd D. Prickett","orcid":"0000-0001-5466-4150","position":40,"is_corresponding":false},{"id":210846,"name":"Vishal N. Koparde","orcid":"0000-0001-8978-8495","position":41,"is_corresponding":false},{"id":980670,"name":"Samantha Sevilla","orcid":"0000-0002-8734-9875","position":42,"is_corresponding":false},{"id":309023,"name":"Skyler A. Kuhn","orcid":"0000-0003-0606-2125","position":43,"is_corresponding":false},{"id":519463,"name":"King C. Chan","orcid":"0000-0002-5355-3501","position":44,"is_corresponding":false},{"id":539693,"name":"Zhonghe Sun","orcid":"0000-0003-0098-3871","position":45,"is_corresponding":false},{"id":1430653,"name":"Nina Bubunenko","orcid":"0009-0001-1386-9640","position":46,"is_corresponding":false},{"id":640652,"name":"Eileen Li","orcid":"0009-0008-7859-1206","position":47,"is_corresponding":false},{"id":570327,"name":"Cathleen Hannah","orcid":"0009-0001-0787-7804","position":48,"is_corresponding":false},{"id":1430654,"name":"Geneti Gaga","orcid":"0009-0002-1743-3403","position":49,"is_corresponding":false},{"id":276014,"name":"Þorkell Andrésson","orcid":"0000-0002-9545-2450","position":50,"is_corresponding":false},{"id":562958,"name":"Maggie Cam","orcid":"0000-0001-8190-9766","position":51,"is_corresponding":false},{"id":255121,"name":"Xiaolin Wu","orcid":"0000-0002-6432-1300","position":52,"is_corresponding":false},{"id":261931,"name":"Lisa M. Jenkins","orcid":"0000-0003-1245-1338","position":53,"is_corresponding":false},{"id":381400,"name":"Andrew M. Blakely","orcid":"0000-0002-5013-3851","position":54,"is_corresponding":false},{"id":243365,"name":"Jeremy L. Davis","orcid":"0000-0002-6334-6936","position":55,"is_corresponding":false},{"id":239671,"name":"Giorgio Trinchieri","orcid":"0000-0001-5892-7464","position":56,"is_corresponding":false},{"id":278626,"name":"Pankaj K. Singh","orcid":"0000-0001-8903-0131","position":57,"is_corresponding":false},{"id":454554,"name":"James C. Yang","orcid":"0000-0001-8935-5008","position":58,"is_corresponding":false},{"id":225422,"name":"Marina Pasca di Magliano","orcid":"0000-0001-9632-9035","position":59,"is_corresponding":false},{"id":106351,"name":"Costas A. Lyssiotis","orcid":"0000-0001-9309-6141","position":60,"is_corresponding":false},{"id":201960,"name":"Michael B Yaffe","orcid":"0000-0002-9547-3251","position":61,"is_corresponding":false},{"id":321383,"name":"Ethan M. Shevach","orcid":"0000-0003-1607-4664","position":62,"is_corresponding":false},{"id":106391,"name":"Jonathan M. Hernandez","orcid":"0000-0001-7529-0557","position":63,"is_corresponding":false},{"id":1407228,"name":"Surajit Sinha","orcid":"0000-0002-7204-2248","position":0,"is_corresponding":true}],"reference_count":129,"raw_metadata":null,"created_at":"2026-07-19T02:52:51.593043Z","pmid":"40736016","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}