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Here we show that ageing reprograms the evolutionary trajectory of\n                    <jats:italic>KRAS<\/jats:italic>\n                    -driven lung adenocarcinoma, limiting primary tumour growth while promoting metastatic dissemination through epigenetic activation of the integrated stress response (ISR). The ISR effector ATF4 drives epithelial and metabolic plasticity, conferring metastatic competence. Mechanistically, aged tumour cells show increased sensitivity to the PERK\u2013eIF2\u03b1 arm of the unfolded protein response, sustaining persistent ATF4 signalling. Targeting ISR\u2013ATF4 genetically or pharmacologically abolishes these adaptations and limits dissemination, whereas ATF4 overexpression alone is sufficient to induce metastasis. The ageing\u2013ATF4 axis imposes a dependency on glutamine metabolism, revealing a therapeutically actionable vulnerability. Clinical analyses confirm that ATF4 is enriched in aged tumours and correlates with poor survival and advanced-stage disease. Collectively, these results define epigenetic ISR\u2013ATF4 activation as a causal driver of lineage plasticity and metastasis in aged tumours, revealing a therapeutic opportunity in older patients with lung adenocarcinoma, the most common yet understudied subset of lung cancer.\n                  <\/jats:p>","DOI":"10.1038\/s41586-026-10216-0","type":"journal-article","created":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T16:06:01Z","timestamp":1773245161000},"page":"1339-1348","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Ageing promotes metastasis via activation of the integrated stress response"],"prefix":"10.1038","volume":"652","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5499-9655","authenticated-orcid":false,"given":"Angana A. 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