Deciphering Radiation-Induced Lung Injury: From Therapeutic Challenges to Macrophage-Centered Molecular Mechanisms and Innovative Interventions

Radiation-induced lung injury (RILI) is a life-threatening complication of thoracic radiation therapy for malignancies. It poses 2 challenges in clinical management: the progression from acute radiation pneumonitis to irreversible pulmonary fibrosis and the limitations of current therapies, such as glucocorticoids and antifibrotic drugs, because of efficacy constraints and adverse effects. Recent studies have revealed that pulmonary macrophages form a spatiotemporally regulated inflammatory-fibrotic coupling network through phenotypic switching. Specifically, alveolar macrophages exhibit M1 proinflammatory polarization during the acute phase, whereas interstitial macrophages transition to M2 profibrotic phenotypes in the chronic phase. This biphasic alveolar macrophages/interstitial macrophages regulatory mechanism provides critical insights for the selection of therapeutic targets. Using this information, drug delivery systems based on nanotechnology-with surface modifications for targeting and drug release-have the potential to change macrophages and related signals in the body, overcoming current treatment limits. This review methodically elucidates recent breakthroughs in radiation-induced lung injury molecular mechanisms and highlights advances in nanomedicine-driven cell-targeted therapies, to provide theoretical foundations for developing multimodal precision intervention strategies.