Lung cancer predominantly affects older individuals, yet how physiological ageing influences tumour evolution remains poorly understood1. Here we show that ageing reprograms the evolutionary trajectory of KRAS-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–eIF2α arm of the unfolded protein response, sustaining persistent ATF4 signalling. Targeting ISR–ATF4 genetically or pharmacologically abolishes these adaptations and limits dissemination, whereas ATF4 overexpression alone is sufficient to induce metastasis. The ageing–ATF4 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–ATF4 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.
肺癌主要影响老年人群，但生理性衰老如何影响肿瘤演化仍知之甚少。本研究发现，衰老会重编程KRAS驱动型肺腺癌的演化轨迹：虽抑制原发性肿瘤生长，却通过表观遗传激活整合应激反应（ISR）促进转移扩散。ISR效应因子ATF4驱动上皮可塑性与代谢可塑性，赋予肿瘤转移潜能。机制研究表明，衰老肿瘤细胞对内质网应激通路的PERK–eIF2α分支敏感性增强，导致ATF4信号持续激活。通过基因编辑或药物靶向ISR–ATF4轴可消除这些适应性变化并抑制扩散，而单纯过表达ATF4即足以诱发转移。衰老-ATF4轴使肿瘤产生对谷氨酰胺代谢的依赖性，揭示了可靶向治疗的新脆弱点。临床分析证实，ATF4在衰老相关肿瘤中高表达，且与患者生存期缩短及进展期病理特征显著相关。综上，本研究证实表观遗传激活ISR–ATF4是衰老肿瘤谱系可塑性与转移的关键驱动因素，为老年肺腺癌（肺癌最常见但研究最不足的亚型）患者提供了治疗新策略。
Ageing promotes metastasis via activation of the integrated stress response
肿瘤(癌症)患者之家