Ageing promotes metastasis via activation of the integrated stress response [RNA-Seq OE]
Lung cancer predominantly affects older individuals, yet how physiological aging influences tumor evolution remains poorly understood. Here, we show that aging reprograms the evolutionary trajectory of KRAS-driven lung adenocarcinoma, limiting primary tumor 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 tumor cells exhibit increased sensitivity to the PERK–eIF2a arm of the unfolded protein response, sustaining persistent ATF4 signaling. Targeting the ISR-ATF4 genetically or pharmacologically abolishes these adaptations and limits dissemination, whereas ATF4 overexpression alone is sufficient to induce metastasis. The aging–ATF4 axis imposes a dependency on glutamine metabolism, revealing a therapeutically actionable vulnerability. Clinical analyses confirm that ATF4 is enriched in aged tumors and correlates with poor survival and advanced-stage disease. Collectively, these results define epigenetic ISR–ATF4 activation as a causal driver of lineage plasticity and metastasis in aged tumors, revealing a therapeutic opportunity in older patients with lung adenocarcinoma, the most common yet understudied subset of lung cancer Overall design: To investigate transcriptomic differences between Old and Young primary cultures from KP-Young and KP-Old mice with and without Atf4 over-expression.