SPP1+ macrophages polarized by lactate confer the progression of hypoxic adaptive tumor cells in brain

作者：Jianlei Zhang, Zhihui Li, Jiang Yin, Weina Fan, Hongfan Liao, Jing Dong, Xianfeng Yu, Yabing Cao, Qiong Zhang, Guopei Zheng, Qianming Yao · 发表于：Neuro-Oncology · 年份：2025 · DOI：10.1093/neuonc/noaf208 · 被引用次数：5 · 研究领域：Cancer, Hypoxia, and Metabolism、Glioma Diagnosis and Treatment、Immune cells in cancer

BACKGROUND: Brain malignancies originating from the central nervous system and metastasizing from extracerebral tumors remain incurable, while the underlying mechanisms remain unclear. In this study, we comprehensively investigated the pan-brain tumor microenvironment. METHODS: We employed transgenic mice, stereotactic brain injections, flow cytometry, CRISPR/Cas9 gene editing, immunohistochemistry, immunofluorescence, quantitative reverse transcription-polymerase chain reaction, western blotting, co-immunoprecipitation, DNA pulldown assays, and chromatin immunoprecipitation. RESULTS: We constructed single-cell RNA sequencing and spatial transcriptome profiles of pan-brain tumors and identified the enhanced hypoxia-inducible factor 1 (HIF-1) signaling in the intracerebral metastases compared with extracerebral parts, as well as in mesenchymal-subtype glioblastomas. Hypoxic adaptability mediated by HIF-1 signaling confers a tumor growth advantage in the brain. Integrated analysis and experimental models revealed the co-localization and mutual dependence between brain tumor hypoxic adaptability and macrophage infiltration. Hypoxic adaptive tumor cells recruit macrophages via galectin 1 (LGALS1) and induce differentiation toward the secreted phosphoprotein 1 (SPP1)+ subpopulation via lactate-mediated histone lactylation. Secreted phosphoprotein 1 directly activates mitogen-activated protein kinase signaling in tumor cells to promote tumor growth and inhibits the cytotoxic activi...