{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T22:12:34Z","timestamp":1791324754361,"version":"4.3.1"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T00:00:00Z","timestamp":1758153600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"National Natural Science Funds","award":["82173189"],"award-info":[{"award-number":["82173189"]}]},{"name":"National Natural Science Funds","award":["82372761"],"award-info":[{"award-number":["82372761"]}]},{"DOI":"10.13039\/501100010226","name":"Educational Commission of Guangdong Province","doi-asserted-by":"publisher","award":["2022ZDZX2049"],"award-info":[{"award-number":["2022ZDZX2049"]}],"id":[{"id":"10.13039\/501100010226","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Science and Technology Program of Guangzhou","award":["2025A03J3834"],"award-info":[{"award-number":["2025A03J3834"]}]},{"name":"Guangzhou Key Medical Discipline Construction Project Fund"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/neuonc\/noaf208","type":"journal-article","created":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T11:40:31Z","timestamp":1758022831000},"page":"70-85","source":"Crossref","is-referenced-by-count":10,"title":["SPP1+ macrophages polarized by lactate confer the progression of hypoxic adaptive tumor cells in brain"],"prefix":"10.1093","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6664-5539","authenticated-orcid":false,"given":"Jianlei","family":"Zhang","sequence":"first","affiliation":[{"name":"Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University , Guangzhou, Guangdong,","place":["China"]},{"name":"Laboratory of Molecular Biology, and Department of Biochemistry, Anhui Medical University , Hefei, Anhui,","place":["China"]},{"name":"Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihui","family":"Li","sequence":"additional","affiliation":[{"name":"Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University , Guangzhou, Guangdong,","place":["China"]},{"name":"Department of Genetics, School of Life Science, Anhui Medical University , Hefei, Anhui,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang","family":"Yin","sequence":"additional","affiliation":[{"name":"Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University , Guangzhou, Guangdong,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weina","family":"Fan","sequence":"additional","affiliation":[{"name":"Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University , Guangzhou, Guangdong,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongfan","family":"Liao","sequence":"additional","affiliation":[{"name":"Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University , Guangzhou, 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