Prophylactic radiotherapy, reshaping the immune microenvironment: Effects, mechanisms and clinical applications for preventing tumor metastasis.

Tumor metastasis remains the leading cause of cancer-related mortality, and effective prevention of clinically occult dissemination remains limited. In the immunotherapy era, the biological role of prophylactic radiotherapy targeting high-risk sites before overt metastasis or regional failure requires critical reassessment. This review summarizes evidence for prophylactic radiotherapy and elective nodal irradiation, distinguishing them from adjuvant radiotherapy and treatment of established but asymptomatic metastases. It further examines the invasion-metastasis cascade, pre-metastatic niche formation, radiation-induced immune microenvironment remodeling, and low-dose hyper-radiosensitivity.

Particular attention is given to low-dose radiotherapy's potential to convert permissive metastatic "soil" into an inhospitable environment, which remains clinically unvalidated. We further discuss major translational barriers, including dose-response windows, toxicity, radiation-induced lymphopenia, biomarker limitations, and integration with immune checkpoint inhibitors. Prophylactic radiotherapy reduces site-specific recurrence but is not universally survival-improving. Future advances require biomarker-enriched trials, lymphocyte-sparing planning, modern imaging surveillance, and mechanistically informed dose and timing selection.