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

Abstract 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.