肿瘤细胞治疗研究
英文原题：Aging reshapes the osteosarcoma ecosystem through immune dysfunction and tumor cell reprogramming.
Aging reshapes the osteosarcoma ecosystem through immune dysfunction and tumor cell reprogramming.
我们的研究揭示了骨肉瘤中免疫和肿瘤内在区室由衰老驱动的协同重塑，其特征为免疫功能障碍和恶性细胞重编程。这些发现为老年OS患者中观察到的较差预后提供了机制性见解，并提示了年龄适应性治疗策略的潜在靶点。
骨肉瘤（OS）是一种高度侵袭性的骨恶性肿瘤，在老年患者中临床结局尤其不佳。然而，衰老如何重塑OS的肿瘤免疫微环境和肿瘤内在程序在很大程度上仍未被探索。本研究旨在描绘OS肿瘤生态系统的年龄相关重塑，并揭示老年患者预后不良的潜在机制。
我们对来自儿童和年轻患者（CYP）以及老年个体的原发OS肿瘤进行了整合的单细胞转录组分析和T细胞受体（TCR）测序。应用了全面的计算分析，包括细胞类型注释、差异丰度分析、拟时序轨迹推断、功能富集和TCR克隆型分析，以系统地表征免疫和恶性区室中与年龄相关的变化。
衰老与OS免疫景观的深刻重塑相关，其特征是促炎和促血管生成的巨噬细胞亚群富集，同时伴有细胞毒性CD8⁺ T细胞和自然杀伤（NK）细胞减少以及TCR库多样性降低。拟时序和功能分析显示，老年患者的巨噬细胞优先采用终末炎症和组织重塑程序，而CYP来源的巨噬细胞则保留较高的翻译和代谢活性。与此同时，肿瘤内在分析揭示了恶性OS细胞中与年龄相关的转录适应，包括应激反应通路、免疫逃逸特征和去分化相关程序的激活。
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.
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