ArticleCancer discovery2025
Functional Reprogramming of Neutrophils within the Brain Tumor Microenvironment by Hypoxia-Driven Histone Lactylation.
Article in Cancer discovery, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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Who cites it
54 citing papers in PubMed.
- Post‑translational modification‑governed immune states in cancer immunity: Biomarker implications for checkpoint competence, tumor visibility and immunotherapy resistance (Review).International journal of oncology · 2026Review
- Neutrophil-driven immunosuppression in cancer.Cell insight · 2026Review
- Glioma microenvironment: Cellular crosstalk, immunosuppression, and novel therapeutic perspectives.Chinese medical journal · 2026Review
- Post-translational modifications in metabolic reprogramming: implications for metabolic therapy and immunotherapy in cancer.Signal transduction and targeted therapy · 2026Review
- Biophysical reprogramming of immunosuppressive neutrophils by cold atmospheric plasma reinvigorates antitumor immunity.Science advances · 2026Article
- The crosstalk between RNA m6A modification and protein lactylation: emerging insights into tumor progression.Oncogene · 2026Review
- Neutrophil-based immunotherapy: A metabolic lens on mechanisms and therapeutic implications.Clinical and translational medicine · 2026Review
- Human immunosuppressive neutrophils: recent answers to old and new questions.The EMBO journal · 2026Review
- Perioperative myeloid cell remodeling shapes CAR-T cell efficacy in glioblastoma.Nature communications · 2026Article
- Protein lactylation in health and diseases: molecular mechanisms, biological significance, and clinical implications.Signal transduction and targeted therapy · 2026Review
- Persistent NET states link lesion-related microbial signals to the cold tumor-related local restrictive environment: a context-dependent working model.Cell communication and signaling : CCS · 2026Review
- Lactylation-driven therapeutic resistance in cancer: Mechanisms and therapeutic opportunities.Genes & diseases · 2026Review
- Metabolic reprogramming of myeloid cells in cancer: from lactate-NAMPT axis to AI-guided therapeutics.Experimental & molecular medicine · 2026Review
- Metabolic Reprogramming and Neurotransmitter Signaling Co-Option in the Glioma Immune Microenvironment: Dual-Axis Regulation of Immunosuppression.Biomolecules · 2026Review
- Transferrin receptor 1: an emerging therapeutic target in cancer beyond iron metabolism.Cancer cell international · 2026Review
- Targeting Lactate and Lactylation in Cancer Metabolism and Immunotherapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Platelet-neutrophil cooperation in cancer: mechanisms of metastatic niche formation and implications for prognostic stratification and therapy.Cellular oncology (Dordrecht, Netherlands) · 2026Review
- Decoding Triphenotypic Neutrophils in Cervical Cancer Evolution and Targeting SPP1+/GBP1+/ELOVL5+ Tumor-Associated Neutrophils to Sensitize Immunotherapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- The hypoxic ECM and neutrophils in MIBC immunotherapy resistance.Nature reviews. Urology · 2026Review
- Targeting WTAP/ROR1/WNT5A-Mediated Crosstalk Between Glioma Stem Cells and Macrophages to Normalize Tumor Vasculature and Enhance Chemotherapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
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20 authors.
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Abstract
Despite functional heterogeneity, the high frequency of intratumoral neutrophils predicts poor clinical outcomes. The tumor microenvironment reprograms neutrophils into immunosuppressive subsets that hinder anticancer immunity, thereby contributing to tumor growth and resistance to immunotherapies. However, the mechanisms underlying neutrophil reprogramming remain elusive. In this study, we report that the immunosuppressive ability of brain tumor-infiltrating neutrophils was restricted to a highly glycolytic and long-lived subset expressing CD71, which acquired immunosuppressive properties in response to hypoxia. Mechanistically, hypoxia boosted glucose metabolism in CD71+ neutrophils, leading to high lactate production. Lactate caused histone lactylation, which subsequently regulated arginase-1 expression, required for T-cell suppression. Targeting histone lactylation with the antiepileptic drug isosafrole blocked CD71+ neutrophil immunosuppressive ability, delayed tumor progression, and sensitized brain tumors to immunotherapy. A distinctive gene signature characterizing immunosuppressive CD71+ neutrophils correlated with adverse clinical outcomes across diverse human malignancies. This study identifies histone lactylation as a potential therapeutic target to counteract neutrophil-induced immunosuppression within tumors. SIGNIFICANCE: Neutrophils are critical contributors to the immunosuppressive microenvironment that restricts the effects of promising immunotherapies in glioblastoma. Our study identifies hypoxia-driven histone lactylation as a potential target to block immunosuppressive neutrophils and boost the effects of immunotherapy in glioblastoma and in other cancer settings beyond brain tumors.
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