Neuro-oncologySep 19, 2025

Lactate-Driven SPP1+ Immune Cells May Promote Growth of Low-Oxygen Adapted Brain Tumor Cells

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 2, 2026

Abstract

Enhanced hypoxia-inducible factor 1 (HIF-1) signaling is observed in intracerebral metastases compared to extracerebral tumors.

Hypoxic adaptability mediated by HIF-1 signaling is associated with a growth advantage for tumors in the brain.
There is co-localization and mutual dependence between hypoxic adaptive tumor cells and macrophage infiltration.
Hypoxic tumor cells recruit macrophages through galectin 1 (LGALS1) and promote differentiation toward a specific subpopulation via lactate-mediated histone modifications.
Secreted phosphoprotein 1 (SPP1) from macrophages activates MAPK signaling in tumor cells, promoting tumor growth and inhibiting CD8+ T cell activity.
Genetic deficiency of SPP1 in macrophages may delay tumor growth under hypoxic conditions and enhance responses to anti-PD-1 therapy.
Targeting lactate dehydrogenase A (LDHA) with stiripentol could impede brain tumor progression and enhance the efficacy of anti-PD-1 therapy.

Simplified

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. SPP1 directly activates mitogen-activated protein kinase (MAPK) 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.