GD2-mediated impairment of macrophage phagocytosis drives pulmonary metastasis in osteosarcoma

<b>Rationale:</b> The lung is the most common site of metastasis in osteosarcoma, with pulmonary dissemination accounting for most of the disease-related mortality. Despite its clinical significance, the underlying mechanisms is poorly defined. <b>Methods:</b> To investigate the clinical relevance of GD2, we performed GD2 immunofluorescence staining on a cohort of human tumor samples. To explore the functional role of GD2 in lung metastasis, we employed an intravenous injection model and an intratibial injection model using U2OS and 143B cells respectively. To elucidate how GD2 regulates osteosarcoma lung metastasis, we carried out an <i>in vitro</i> flow-based phagocytosis assay. <b>Results:</b> We identify the disialoganglioside GD2 as a key mediator of osteosarcoma lung metastasis through impairing macrophage phagocytic function. Mechanistically, GD2 interacts with SIGLECE in mice (or SIGLEC7 in humans) on the cell surface of macrophages, leading to the activation of SH2-containing protein tyrosine phosphatase 2 (SHP2), which in turn suppresses macrophage phagocytic function. Notably, co-treatment with an anti-GD2 antibody and the SHP2 inhibitor SHP099 resulted in a synergistic reduction of lung metastasis. <b>Conclusion:</b> Our findings uncover a mechanism of osteosarcoma lung metastasis and highlight the GD2-SIGLEC-SHP2 axis as a promising therapeutic target.