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

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 activity of CD8+ T cells. Genetic SPP1 deficiency in macrophages delays hypoxic adaptive tumor growth in the brain and enhances the tumor response to anti-programmed cell death-1 (anti-PD-1) therapy. Preclinically, targeting lactate dehydrogenase A (LDHA) by stiripentol with blood-brain barrier permeability impedes brain tumor progression and synergizes with anti-PD-1 therapy. CONCLUSIONS: The interrelationship between hypoxic adaptive tumor cells and macrophages in the brain highlights the possibility of SPP1+ macrophage-based microenvironment remodeling in brain tumor therapy.