Radiation therapy, a cornerstone of cancer treatment, can inadvertently fuel the growth of existing metastases, according to a study published online in Nature. This surprising finding challenges conventional wisdom and opens new avenues for improving treatment strategies.
How Radiation Can Backfire in Advanced Cancers
A new study reveals a mechanism by which radiation therapy can promote the spread of cancer, highlighting the need for combination therapies.
- Researchers at the University of Chicago discovered that radiation therapy can trigger the release of a molecule called amphiregulin in tumor cells.
- Amphiregulin appears to reprogram immune cells, making them less effective at fighting cancer and potentially increasing metastasis.
- Blocking amphiregulin in combination with radiation therapy showed promising results in reducing both tumor size and the number of metastatic sites in laboratory models.
- Patients with higher levels of amphiregulin expression in their tumors experienced shorter progression-free and overall survival times.
András Piffkó, M.D., and colleagues at the University of Chicago investigated this unexpected effect of radiation in patients with advanced solid tumors who received stereotactic body radiotherapy targeting multiple metastatic sites. The team analyzed gene expression in 22 matched sets of biopsies taken before and after radiation treatment.
The research revealed that radiation induces the production of amphiregulin within tumor cells. This molecule then alters the behavior of immune cells expressing the epidermal growth factor receptor (EGFR), shifting them toward an immunosuppressive state and hindering their ability to destroy cancer cells. Amphiregulin was identified as a key player in three of the top 20 gene pathways associated with distant tumor progression.
Interestingly, patients whose tumors exhibited increased amphiregulin levels following radiation therapy had poorer outcomes, experiencing shorter periods without disease progression and reduced overall survival. Local radiotherapy, while initially reducing the number of lung metastases, ultimately led to an increase in their size due to the secretion of amphiregulin. However, when the gene responsible for amphiregulin production was deactivated, this effect was prevented.
Did you know? Amphiregulin is a signaling molecule that plays a role in wound healing and tissue repair, but its role in cancer progression is only recently being understood.
Similar findings were observed in mouse models of lung metastasis. Crucially, blocking amphiregulin effectively reversed the pro-metastatic effects of radiation. “Interestingly, the combination of radiation and amphiregulin blockade decreased both tumor size and the number of metastatic sites,” explained senior author Ralph R. Weichselbaum, M.D., also from the University of Chicago.
Several authors have disclosed financial relationships with the biopharmaceutical industry.
More information: András Piffkó et al, Radiation-induced amphiregulin drives tumour metastasis, Nature (2025). DOI: 10.1038/s41586-025-08994-0
