Aging reshapes the osteosarcoma ecosystem through immune dysfunction and tumor cell reprogramming.
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PURPOSE: Osteosarcoma (OS) is a highly aggressive bone malignancy with particularly poor clinical outcomes in elderly patients. However, how aging reshapes the tumor immune microenvironment and tumor-intrinsic programs in OS remains largely unexplored. This study aimed to delineate age-associated remodeling of the OS tumor ecosystem and to uncover mechanisms underlying the unfavorable prognosis of elderly patients. METHODS: We performed integrated single-cell transcriptomic profiling and T cell receptor (TCR) sequencing on primary OS tumors obtained from children and young patients (CYP) and elderly individuals. Comprehensive computational analyses, including cell-type annotation, differential abundance analysis, pseudotime trajectory inference, functional enrichment, and TCR clonotype analysis, were applied to systematically characterize age-related changes across immune and malignant compartments. RESULTS: Aging was associated with a profound reorganization of the OS immune landscape, characterized by enrichment of pro-inflammatory and pro-angiogenic macrophage subsets, accompanied by contraction of cytotoxic CD8⁺ T cells and natural killer (NK) cells and reduced TCR repertoire diversity. Pseudotime and functional analyses revealed that macrophages from elderly patients preferentially adopted terminal inflammatory and tissue-remodeling programs, whereas CYP-derived macrophages retained higher translational and metabolic activity. In parallel, tumor-intrinsic analyses uncovered age-associated transcriptional adaptations in malignant OS cells, including activation of stress-response pathways, immune evasion signatures, and dedifferentiation-related programs. CONCLUSIONS: Our study reveals coordinated aging-driven remodeling of both immune and tumor-intrinsic compartments in osteosarcoma, marked by immune dysfunction and malignant cell reprogramming. These findings provide mechanistic insight into the poor prognosis observed in elderly OS patients and suggest potential targets for age-adapted therapeutic strategies.