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Recent scientific data recognize the B7-H3 checkpoint molecule as a potential target for immunotherapy of pediatric solid tumors (PSTs). B7-H3 is highly expressed in extracranial PSTs such as neuroblastoma, rhabdomyosarcoma, nephroblastoma, osteosarcoma, and Ewing sarcoma, whereas its expression is absent or very low in normal tissues and organs. The influence of B7-H3 on the biological behavior of malignant solid neoplasms of childhood is expressed through different molecular mechanisms, including stimulation of immune evasion and tumor invasion, and cell-cycle disruption. It has been shown that B7-H3 knockdown decreased tumor cell proliferation and migration, suppressed tumor growth, and enhanced anti-tumor immune response in some pediatric solid cancers. Antibody-drug conjugates targeting B7-H3 exhibited profound anti-tumor effects against preclinical models of pediatric solid malignancies. Moreover, B7-H3-targeting chimeric antigen receptor (CAR)-T cells demonstrated significant in vivo activity against different xenograft models of neuroblastoma, Ewing sarcoma, and osteosarcoma. Finally, clinical studies demonstrated the potent anti-tumor activity of B7-H3-targeting antibody-radioimmunoconjugates in metastatic neuroblastoma. This review summarizes the established data from various PST-related studies, including in vitro, in vivo, and clinical research, and explains all the benefits and potential obstacles of targeting B7-H3 by novel immunotherapeutic agents designed to treat malignant extracranial solid tumors of childhood. [ABSTRACT FROM AUTHOR]