Radiotherapy (RT), while pivotal in cancer control, may paradoxically promote metastasis through systemic effects. Emerging evidence implicates RT-induced growth factors and immune modulation-especially via amphiregulin-epidermal growth factor receptor (EGFR) signaling-in facilitating metastatic outgrowth at distant sites. This effect underscores the need to refine RT strategies, identify high-risk patients, and explore therapeutic combinations targeting myeloid cells and EGFR pathways to mitigate pro-metastatic consequences and optimize outcomes in the immunotherapy era.

Declaration of interests R.R.W. has stock and other ownership interests with Boost Therapeutics, Immvira, Reflexion Pharmaceuticals, Coordination Pharmaceuticals, Magi Therapeutics, Fuse Biotherapeutics and Oncosenescence. He has served in a consulting or advisory role for Aettis, Astrazeneca, Coordination Pharmaceuticals, Genus, Merck Serono S.A., Nanoproteagen, NKMax America, and Shuttle Pharmaceuticals. He has received research grant funding from Varian and Regeneron, as well as NIH funding (R01CA262508 and U54 CA274291). He has received compensation including travel, accommodations, or expense reimbursement from Astrazeneca, Boehringer Ingelheim, and Merck Serono S.A. S.P.P. has received research grant funding from the LUNGevity Foundation, Cancer Research Foundation, Falk Medical Research Trust, and American Lung Association. R.R.W. and S.P.P. are co-founders of PersonaDx and have a patent pending entitled “Methods and Kits for Diagnosis and Triage of Patients with Colorectal Liver Metastases” (PCT/US2019/028071). A.P., S.P.P., and R.R.W. have filed a patent on amphiregulin in the radiation response.