Sung Ji-Yong, Hwang Kihwan
Department of Neurosurgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam-si 13620, Republic of Korea.
Int J Mol Sci. 2025 Aug 1;26(15):7411. doi: 10.3390/ijms26157411.
Glioblastoma (GBM) is a highly aggressive and heterogeneous brain tumor. Glioma stem-like cells (GSCs) play a central role in tumor progression, therapeutic resistance, and recurrence. Although immune cells are known to shape the GBM microenvironment, the impact of antigen-presenting-cell (APC) signature genes on tumor-intrinsic phenotypes remains underexplored. We analyzed both bulk- and single-cell RNA sequencing datasets of GBM to investigate the association between APC gene expression and tumor-cell states, including stemness and metabolic reprogramming. Signature scores were computed using curated gene sets related to APC activity, KEGG metabolic pathways, and cancer hallmark pathways. Protein-protein interaction (PPI) networks were constructed to examine the links between immune regulators and metabolic programs. The high expression of APC-related genes, such as HLA-DRA, CD74, CD80, CD86, and CIITA, was associated with lower stemness signatures and enhanced inflammatory signaling. These APC-high states (mean difference = -0.43, adjusted < 0.001) also showed a shift in metabolic activity, with decreased oxidative phosphorylation and increased lipid and steroid metabolism. This pattern suggests coordinated changes in immune activity and metabolic status. Furthermore, TNF-α and other inflammatory markers were more highly expressed in the less stem-like tumor cells, indicating a possible role of inflammation in promoting differentiation. Our findings revealed that elevated APC gene signatures are associated with more differentiated and metabolically specialized GBM cell states. These transcriptional features may also reflect greater immunogenicity and inflammation sensitivity. The APC metabolic signature may serve as a useful biomarker to identify GBM subpopulations with reduced stemness and increased immune engagement, offering potential therapeutic implications.
胶质母细胞瘤（GBM）是一种极具侵袭性且异质性的脑肿瘤。胶质瘤干细胞样细胞（GSCs）在肿瘤进展、治疗抵抗和复发中起着核心作用。尽管已知免疫细胞塑造了GBM的微环境，但抗原呈递细胞（APC）特征基因对肿瘤内在表型的影响仍未得到充分探索。我们分析了GBM的批量和单细胞RNA测序数据集，以研究APC基因表达与肿瘤细胞状态之间的关联，包括干性和代谢重编程。使用与APC活性、KEGG代谢途径和癌症特征途径相关的精选基因集计算特征分数。构建蛋白质-蛋白质相互作用（PPI）网络以检查免疫调节因子与代谢程序之间的联系。APC相关基因，如HLA-DRA、CD74、CD80、CD86和CIITA的高表达与较低的干性特征和增强的炎症信号相关。这些APC高表达状态（平均差异=-0.43，校正后<0.001）也显示出代谢活性的转变，氧化磷酸化减少，脂质和类固醇代谢增加。这种模式表明免疫活性和代谢状态的协调变化。此外，TNF-α和其他炎症标志物在干性较低的肿瘤细胞中表达更高，表明炎症在促进分化中可能发挥作用。我们的研究结果表明，APC基因特征升高与更分化和代谢更特化的GBM细胞状态相关。这些转录特征也可能反映出更高的免疫原性和炎症敏感性。APC代谢特征可能作为一种有用的生物标志物，用于识别干性降低和免疫参与增加的GBM亚群，具有潜在的治疗意义。
