哥德堡大学Volkan I. Sayin团队在研究中取得进展。他们揭示了衰老通过激活综合应激反应促进转移。相关论文于2026年3月11日发表在《自然》杂志上。

本研究表明，衰老重新编程了KRAS驱动的肺腺癌的进化轨迹，限制了原发肿瘤的生长，同时通过表观遗传激活综合应激反应（ISR）促进转移性传播。ISR效应物ATF4驱动上皮和代谢可塑性，赋予转移能力。从机制上讲，衰老的肿瘤细胞对未折叠蛋白反应的PERK-eIF2α臂的敏感性增加，从而维持了持续的ATF4信号传导。以ISR-ATF4为靶点在基因或药理学上消除了这些适应性并限制了传播，而ATF4过表达本身就足以诱导转移。老化-ATF4轴对谷氨酰胺代谢施加依赖性，揭示了治疗上可行的脆弱性。临床分析证实，ATF4在老年肿瘤中富集，并与生存差和晚期疾病相关。总的来说，这些结果将表观遗传ISR-ATF4激活定义为老年肿瘤谱系可塑性和转移的诱导驱动因素，揭示了老年肺腺癌患者的治疗机会，肺腺癌是肺癌中最常见但研究不足的亚群。

据介绍，肺癌主要影响老年人，然而生理衰老如何影响肿瘤的进化仍然知之甚少。

附：英文原文

Title: Ageing promotes metastasis via activation of the integrated stress response

Author: Patel, Angana A. H., Dzanan, Jozefina J., Ali, Kevin X., Eklund, Ella A., Alvarez, Samantha W., Raj, Dorota, Dankis, Martin, Altinnder, Ilayda, Schwarz, Maria, Le Gal, Kristell, Bedel, Emre, El Zowalaty, Ahmed Ezat, Jonasson, Emma, Albatrok, Heba, Gul, Nadia, Bossowski, Jozef P., Pillai, Ray, Micke, Patrick, Botling, Johan, Akyrek, Levent M., Angeletti, Davide, Sayin, Sama I., Hrtlova, Anetta, Papagiannakopoulos, Thales, Olofsson Bagge, Roger, Sthlberg, Anders, Hallqvist, Andreas, Wiel, Clotilde, Sayin, Volkan I.

Issue&Volume: 2026-03-11

Abstract: 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.

DOI: 10.1038/s41586-026-10216-0

Source: https://www.nature.com/articles/s41586-026-10216-0