Synergistic composite engineering: Bridging immunomodulaftion, bone regeneration and precision therapy in osteosarcoma management

Osteosarcoma is the most common primary malignant bone tumor. It presents two major clinical challenges: aggressive tumor progression and extensive bone destruction. Traditional treatments often fail to achieve both complete tumor eradication and effective skeletal reconstruction. Recent advances in multifunctional composite biomaterials have made it possible to integrate tumor ablation, immune modulation, and bone regeneration into unified therapeutic systems. This review classifies these platforms according to material dimensionality (nanoscale, microscale, and macroscale) and examines targeted delivery strategies, including responsive release, external stimuli, and monofunctional optimization. We also highlight emerging synergistic systems that combine photothermal therapy, chemotherapy, metabolic interference, gene regulation, and mechanical support to produce coordinated therapeutic effects. Particular attention is given to metabolic–bone coupling and gene–mechanical synergy, which represent new strategies for simultaneously inhibiting tumor progression and promoting osteogenesis. Building on our original framework, we now map the osteosarcoma immune microenvironment and highlight precision immunoregulation enabled by materials, targeting T lymphocytes, natural killer cells, the axis of tumor associated macrophages and osteoclasts, and dendritic cells and B lymphocytes, to better couple tumor control with bone regeneration. Finally, we outline key translational challenges—such as mismatched degradation and therapeutic windows, tumor-promoting effects of osteogenic signaling, and biological heterogeneity—and propose future directions for developing precision-engineered, adaptive platforms for osteosarcoma management.