Radiation-induced amphiregulin drives tumour metastasis PMID: 40369065

ADC Targets in Oncology

2026-04-10

Radiation-induced amphiregulin drives tumour metastasis

Nature. 2025 Jul;643(8072):810-819. doi: 10.1038/s41586-025-08994-0.

András Piffkó ^# ¹ ² ³ , Kaiting Yang ^# ¹ ² ⁴ , Arpit Panda ^# ⁵ ⁶ , Janna Heide ⁷ , Krystyna Tesak ¹ ² ⁵ , Chuangyu Wen ¹ ² , Katarzyna Zawieracz ⁸ , Liangliang Wang ¹ ² ⁹ , Emile Z Naccasha ¹ ² , Jason Bugno ¹ ² ¹⁰ , Yanbin Fu ¹ ² ¹¹ , Dapeng Chen ¹ ² , Leonhard Donle ⁷ , Ernst Lengyel ⁷ , Douglas G Tilley ¹² , Matthias Mack ¹³ , Ronald S Rock ⁵ , Steven J Chmura ¹ ² , Everett E Vokes ¹⁴ , Chuan He ⁵ ⁶ , Sean P Pitroda ^# ¹ ² , Hua Laura Liang ^# ¹ ² , Ralph R Weichselbaum ^# ¹⁵ ¹⁶

Affiliations

1. Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL, USA.
2. The Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL, USA.
3. Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
4. School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, P. R. China.
5. Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, University of Chicago, Chicago, IL, USA.
6. Howard Hughes Medical Institute, University of Chicago, Chicago, IL, USA.
7. Department of Obstetrics and Gynecology/Section Gynecologic Oncology, University of Chicago, Chicago, IL, USA.
8. Department of Pathology, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
9. The Laboratory of Microbiome and Microecological Technology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, P. R. China.
10. Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, Chicago, IL, USA.
11. Drukier Institute for Children's Health, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.
12. Department of Cardiovascular Sciences, Temple University, Philadelphia, PA, USA.
13. Department of Internal Medicine, University of Regensburg, Regensburg, Germany.
14. Department of Medicine, University of Chicago, Chicago, IL, USA.
15. Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL, USA. [email protected].
16. The Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL, USA. [email protected].
# Contributed equally.

Abstract

The anti-tumour effect of radiotherapy beyond the treatment field-the abscopal effect-has garnered much interest¹. However, the potentially deleterious effect of radiation in promoting metastasis is less well studied. Here we show that radiotherapy induces the expression of the EGFR ligand Amphiregulin in tumour cells, which reprogrammes EGFR-expressing myeloid cells toward an immunosuppressive phenotype and reduces phagocytosis. This stimulates distant metastasis growth in human patients and in pre-clinical mouse tumour models. The inhibition of these tumour-promoting factors induced by radiotherapy may represent a novel therapeutic strategy to improve patient outcomes.