A new study reveals how aging changes the biological behavior of lung cancer.
Scientists at the University of Gothenburg have identified a protein that may increase the risk of lung cancer spreading and returning after treatment. Their findings suggest a possible path toward more targeted therapies, especially for older patients.
Lung cancer is most common in older adults. Yet many laboratory studies still rely on experiments using young animals.
To better represent how the disease behaves in real life, the research team compared lung tumors from young and older mice. They also analyzed medical data from about 1,000 lung cancer patients in the Swedish regions of Halland and Västra Götaland.
The results, published in the journal Nature, revealed a consistent pattern. In older individuals, tumors were typically smaller and grew more slowly. Despite this slower growth, the disease was often more advanced at the time of diagnosis and had spread to other organs more frequently.
“This helps explain a paradox that physicians often observe that older patients may be diagnosed with a small and slowly growing primary tumor that has nevertheless already spread far beyond the lung, for example to the brain, liver, and bones,” says Volkan Sayin, Associate Professor at the University of Gothenburg.
A hijacked stress-response system
The research shows that aging changes the biological behavior of lung cancer, making tumors more likely to spread. The team identified a molecular signaling pathway that plays an important role in this process. At the center of this pathway is a stress-response protein known as ATF4.
Under normal conditions, ATF4 helps control the “integrated stress response.” This system helps cells cope with challenges such as nutrient shortages, viral particles, or the buildup of misfolded proteins by activating protective and repair processes, explains Volkan Sayin.
“In older patients, this stress response is hijacked by the tumor, allowing cancer cells to reprogram their metabolism. The tumor does not grow faster, but this metabolic rewiring enables the cancer cells to spread and form metastases in other parts of the body,” he says.
The researchers found higher ATF4 levels in tumors from older subjects, both in mice and in human patients. Elevated ATF4 was also linked to a greater chance of cancer returning after lung surgery and lower survival rates among people with lung adenocarcinoma, the most common type of lung cancer.
“Our results suggest that ATF4 is not only part of the mechanism behind the spread of lung cancer but may also serve as a marker of more aggressive disease,” says Clotilde Wiel, Associate Professor at the University of Gothenburg.
A new treatment strategy
The findings also suggest a new strategy for treatment by targeting the age-related signaling pathway used by tumors. When researchers blocked ATF4, or a metabolic process controlled by ATF4, with drugs, the spread of tumors in older mice was dramatically reduced.
Scientists have previously struggled to understand why similar drugs have not worked well in human trials. This study suggests the problem may be that the treatments were not directed at the patients most likely to benefit.
“Our results indicate that these drugs may work significantly better if used more precisely, for example in older patients whose tumors show high ATF4 activity,” says Clotilde Wiel.
Biological aging overlooked
Many current cancer treatments, including chemotherapy and radiation therapy, are designed to attack rapidly growing tumors. However, the types of lung tumors most common in older adults often grow more slowly.
The researchers say cancer research and drug development need to place greater focus on the biological effects of aging.
“It is very clear that normal aging fundamentally changes how tumors develop, a field of research where we currently lack a lot of knowledge. Indeed, relatively little cancer research is conducted in age-appropriate models, as such studies are both very expensive and take a long time,” concludes Volkan Sayin.
Reference: “Ageing promotes metastasis via activation of the integrated stress response” by Angana A. H. Patel, Jozefina J. Dzanan, Kevin X. Ali, Ella A. Eklund, Samantha W. Alvarez, Dorota Raj, Martin Dankis, Ilayda Altinönder, Maria Schwarz, Kristell Le Gal, Emre Bedel, Ahmed Ezat El Zowalaty, Emma Jonasson, Heba Albatrok, Nadia Gul, Jozef P. Bossowski, Ray Pillai, Patrick Micke, Johan Botling, Levent M. Akyürek, Davide Angeletti, Sama I. Sayin, Anetta Härtlova, Thales Papagiannakopoulos, Roger Olofsson Bagge, Anders Ståhlberg, Andreas Hallqvist, Clotilde Wiel and Volkan I. Sayin, 11 March 2026, Nature.
DOI: 10.1038/s41586-026-10216-0
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