Amphiregulin as a Mediator of Radiation-Induced Systemic Effects in Metastatic Cancer: Balancing Local Control with...

Metastasis-directed therapies such as stereotactic body radiotherapy (SBRT) are increasingly used in patients with metastatic cancer with limited disease burden. Although effective for local control, emerging evidence suggests that SBRT may have unintended systemic effects that reshape the tumor-immune landscape. A recent study identifies amphiregulin (AREG), an EGFR ligand, as a key mediator of radiation-induced changes in metastatic behavior. In clinical cohorts and murine models, SBRT led to marked AREG upregulation. Rather than promoting tumor cell proliferation directly, AREG acted through the myeloid compartment, inducing monocyte differentiation into immunosuppressive macrophages and enabling immune escape. Elevated AREG-either at baseline or following SBRT-was associated with increased metastatic progression and inferior survival. Mechanistically, AREG signaling induced CD47 expression on tumor cells, further impairing macrophage-mediated clearance. Therapeutically, AREG blockade, especially combined with anti-CD47 antibodies, synergized with radiotherapy to suppress both local and distant diseases in preclinical models. These findings reveal both challenges and opportunities: whereas radiation effectively suppresses new metastatic seeding, it may reorganize the biological ecosystem in ways that unmask dormant disease. Understanding these dual effects offers therapeutic opportunities through combination approaches targeting radiation-induced pathways. AREG emerges as both a biomarker and therapeutic target. Integrating biomarker-informed strategies with metastasis-directed therapies may be essential for achieving durable disease control and optimizing outcomes in metastatic cancer.