This research identifies physiological ageing as a primary driver of metastasis in lung adenocarcinoma by altering the evolutionary path of cancer cells. While older subjects exhibit slower-growing primary tumors, the study reveals that ageing triggers epigenetic changes that activate the integrated stress response (ISR) and its master effector, ATF4. This signaling pathway causes cellular plasticity and resistance to cell death, allowing cancer to spread more aggressively to distant organs. The activation of ATF4 also creates a specific metabolic reliance on glutamine, making these advanced tumors uniquely vulnerable to glutaminase inhibitors. By utilizing both mouse models and human clinical data, the authors demonstrate that targeting the ISR–ATF4 axis can effectively block the spread of cancer. These findings offer a potential therapeutic strategy specifically tailored for older patients, a group that is often overlooked in traditional cancer research.

References:

• Patel A A H, Dzanan J J, Ali K X, et al. Ageing promotes metastasis via activation of the integrated stress response[J]. Nature, 2026: 1-10.