While radiation therapy is an effective tool to destroy cancer cells, new research from Vanderbilt researchers suggests that in an aggressive form of breast cancer, it may also trigger a protective cellular response that may explain why our current therapies fail some patients.
In a study led by Marjan Rafat, assistant professor of chemical and biomolecular engineering and biomedical engineering, and published in Cell Reports, researchers found that radiation therapy activates a process called autophagy in surrounding fibroblasts—cells that support and structure breast tissue. While autophagy helps these cells survive the stress of treatment, the Vanderbilt team found it also alters the surrounding tissue in ways that can make nearby cancer cells more aggressive. Vanderbilt doctoral graduate Kevin Corn led and conducted much of the study’s experimental work.
These findings point to a potential new therapeutic approach: targeting autophagy in surrounding fibroblasts to help reduce recurrence in triple-negative breast cancer (TNBC), one of the most aggressive and difficult-to-treat forms of the disease.
A protective process with unintended consequences
Autophagy is a natural cellular process that allows cells to recycle damaged components and adapt to stress, including radiation exposure. In fibroblasts, the team found that this process becomes highly active after treatment. That response helps the cells survive—but it also changes how they behave.
The researchers showed that irradiated fibroblasts begin releasing signaling molecules and metabolic byproducts that encourage nearby cancer cells to become more aggressive. TNBC cells exposed to these signals moved faster and formed larger tumor-like structures.
“When we think about radiation, we usually focus on tumor cells,” Rafat said. “But the surrounding tissue is also responding, and that can shape what happens after treatment.”
Following radiation exposure, fibroblasts shift into a higher-energy state, boosting mitochondrial activity and changing how they process nutrients. These changes are regulated by autophagy and lead to the release of inflammatory signals such as IL-6, which are known to influence tumor behavior.
Together, these changes reshape the tumor microenvironment—creating conditions that may help cancer cells survive and spread after treatment.
Yet, when the researchers blocked autophagy in fibroblasts, those tumor-promoting signals dropped off, and cancer cells showed reduced migration and growth in experimental models.
These findings suggest that combining radiation therapy with drugs that target autophagy could help limit recurrence. Several autophagy-inhibiting compounds are already being studied in cancer clinical trials.
“For patients with aggressive cancers like triple-negative breast cancer, recurrence remains a major challenge,” Corn said. “Our work suggests that targeting how normal tissue responds to radiation could be part of the solution.”
Engineering insight into cancer biology
The study also shows how engineering approaches can help uncover aspects of disease that are easy to miss. By combining metabolic analysis, imaging, and cancer biology, the Vanderbilt team mapped how stress responses in healthy cells can influence cancer outcomes.
“This is a good example of how looking beyond the tumor itself can reveal new strategies for treatment,” Rafat said. “If we can better understand—and control—the surrounding environment, we may be able to improve patient outcomes.”
The research was conducted through collaborations across Vanderbilt University and Vanderbilt University Medical Center and was supported by the National Institutes of Health and the American Cancer Society.