Exploiting B7-H3: Molecular Insights and Immunotherapeutic Strategies for Osteosarcoma

Osteosarcoma (OS) remains the most common primary malignant bone tumor in adolescents, with conventional treatments yielding only modest improvements in long-term survival. Immunotherapy has emerged as a promising strategy to overcome these limitations. B7-H3 (CD276) stands apart from other potential targets due to its high expression in tumors cells, as well as its strong association with tumor aggressiveness and poor prognosis. This review provides a comprehensive overview of B7-H3, covering its molecular structure, regulatory mechanisms, biological functions, and expression patterns in tumor tissues. We emphasize the dual roles of B7-H3-both immunoregulatory and non-immunoregulatory-in shaping the tumor microenvironment (TME) and facilitating immune evasion. Building on these insights, we summarize current immunotherapeutic strategies targeting B7-H3 in OS, including monoclonal antibodies (mAbs), chimeric antigen receptor T cells (CAR-T), antibody-drug conjugates (ADCs), and bispecific antibodies (bsAbs). These four strategies have their own advantages and deficiencies. Excitingly, rapid advances in nanoparticle-based systems offer promising solutions to overcome the limitations, especially to develop more effective drug delivery systems and to reshape the TME by targeting immune cells. Despite promising progress, significant challenges remain. These include the absence of an identified B7-H3 receptor, the immunosuppressive and heterogeneous nature of the OS TME, and the need for improved targeting specificity and safety. Addressing these challenges through optimization of delivery systems, combination strategies, and the integration of nanotechnology may unlock the full potential of B7-H3-based immunotherapy in the treatment of OS.