Immunomodulation in the repair of osteonecrosis of the femoral head: reprogramming strategies for macrophages and immune cells

Longfei Han, Mingli Han, Wenyuan Hou, Guifeng Luo, Long Tian, M Li, Hai Su, Mincong He, Fan Yang, Hu Wei, Qiushi Wei

Osteonecrosis of the femoral head (ONFH) is a severe and debilitating disease that substantially affects patients’ functional capacity and daily activities. Within necrotic femoral heads, immune cells, particularly macrophages, undergo phenotypic reprogramming. This phenotypic shift in macrophages, along with their interactions with other cell types—including osteoclasts, mesenchymal stem cells, and endothelial cells—collectively mediates disease progression. However, targeted immunotherapeutic strategies remain poorly defined. In this context, the present study reviews recent literature and provides a comprehensive overview of the immunological landscape of macrophages in osteonecrosis of the femoral head (ONFH). It summarizes current knowledge on macrophage immune reprogramming, intercellular interactions with neighboring cells (such as mesenchymal stem cells, osteoclasts, and vascular endothelial cells), and the cellular composition of immune cells (including neutrophils, B cells, and T cells) in ONFH. Furthermore, it explores the potential application of biomaterials developed through various strategies for ONFH treatment. Emerging evidence indicates that the direction of macrophage polarization and their intercellular interactions with diverse cell types (e.g., mesenchymal stem cells, osteoclasts, and vascular endothelial cells), together with the infiltration of immune cells (such as neutrophils, B cells, and T cells), collectively influence the progression of ONFH. On this basis, therapeutic strategies targeting macrophage polarization and immune cell activation are proposed, with a particular focus on biomaterials possessing diverse physicochemical properties, thereby offering insights to facilitate the clinical translation of ONFH treatments.