{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T18:22:37Z","timestamp":1790619757646,"version":"4.1.0"},"reference-count":49,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:00:00Z","timestamp":1782691200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":79,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Fujian Provincial Department of Education Fund","award":["JAT220106"],"award-info":[{"award-number":["JAT220106"]}]},{"name":"Putian Science and Technology Program Project","award":["2024S3f002"],"award-info":[{"award-number":["2024S3f002"]}]},{"name":"Joint Funds for Innovation of Science and Technology, Fujian Province","award":["2023Y9198"],"award-info":[{"award-number":["2023Y9198"]}]},{"name":"Natural Science Foundation of Fujian Province","award":["2025J01770"],"award-info":[{"award-number":["2025J01770"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Neuroinflammation"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Recurrent glioblastoma (rGBM) is characterized by marked myeloid remodeling and a profoundly immunosuppressive microenvironment. Although carbonic anhydrase 9 (CA9) is a canonical hypoxia-inducible molecule linked to aggressive glioblastoma (GBM) behavior, its cell-state-specific distribution in rGBM and its role in glioma stem cell (GSC)-macrophage crosstalk remain incompletely understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We integrated public transcriptomic cohorts, single-cell RNA sequencing, quantitative proteomics, paired clinical specimens, and in vitro\/in vivo functional assays to define the role of CA9 in rGBM. Malignant-cell states and tumor-associated macrophage (TAM) subpopulations were resolved at single-cell resolution, and intercellular communication was inferred computationally. CA9 gain- and loss-of-function models were established in GBM cell lines and patient-derived GSCs. ANXA1 expression and secretion were assessed by qRT-PCR, Western blotting, ELISA, and promoter-reporter assays. Macrophage polarization was evaluated using conditioned-medium transfer, recombinant ANXA1 rescue, and pharmacological FPR1 blockade with cyclosporin H.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>CA9 was upregulated in GBM, further enriched in mesenchymal and recurrent tumors, and associated with inferior survival. Single-cell analysis localized CA9 predominantly to a hypoxia-associated MES-like GSC subpopulation that expanded in recurrent samples and exhibited elevated stemness. Recurrent tumors also displayed increased SPP1\u2009+\u2009immunosuppressive TAMs. Proteomic, transcriptomic, and cell\u2013cell communication analyses prioritized ANXA1 as a CA9-associated downstream mediator with secreted immunomodulatory potential. Hypoxia induced both CA9 and ANXA1, and mutation of a hypoxia-response element attenuated ANXA1 promoter activation. CA9 depletion reduced ANXA1 expression and secretion, impaired GBM growth phenotypes, and attenuated hypoxia-driven ANXA1 induction. CellChat highlighted enhanced signaling between hypoxic MES-like GSCs and SPP1\u2009+\u2009TAMs in recurrent GBM, nominating ANXA1-FPR1 as a leading ligand-receptor axis. Functionally, conditioned medium from CA9-high GBM cells promoted M2-like macrophage polarization, which was weakened by CA9 knockdown, partially restored by recombinant ANXA1, and markedly suppressed by FPR1 antagonism, supporting ANXA1 as a contributory paracrine mediator, and markedly suppressed by FPR1 antagonism. In vivo, CA9 depletion, and in CA9-intact tumors FPR1 blockade, reduced M2-like macrophage-associated signals.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>CA9 is enriched in hypoxic MES-like GSCs in rGBM and promotes an ANXA1-dependent paracrine program that supports immunosuppressive macrophage polarization. These findings identify a CA9-ANXA1-FPR1-associated neuroimmune crosstalk axis linking hypoxic stem-like tumor states to myeloid remodeling in recurrent GBM, with ANXA1 functioning as a contributory paracrine mediator rather than a sole effector of CA9-driven immunosuppression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical abstract<\/jats:title>\n                    <jats:p>In recurrent glioblastoma, CA9 is preferentially enriched in hypoxia-associated MES-like glioma stem cells. Elevated CA9 enhances ANXA1 expression and secretion under hypoxic conditions. Secreted ANXA1 engages FPR1-associated signaling in SPP1\u2009+\u2009tumor-associated macrophages, promoting an M2-like immunosuppressive phenotype. This tumor-to-myeloid paracrine circuit contributes to neuroimmune remodeling and supports recurrent GBM progression.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12974-026-03905-0","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T13:19:03Z","timestamp":1782739143000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Hypoxic CA9-high mesenchymal-like glioma stem cells promote ANXA1-FPR1-dependent macrophage polarization in recurrent glioblastoma"],"prefix":"10.1186","volume":"23","author":[{"given":"Hangqi","family":"Gao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guiting","family":"You","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhuang","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijing","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiexin","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Risheng","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caihou","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,29]]},"reference":[{"issue":"8","key":"3905_CR1","doi-asserted-by":"publisher","first-page":"1231","DOI":"10.1093\/neuonc\/noab106","volume":"23","author":"DN Louis","year":"2021","unstructured":"Louis DN, Perry A, Wesseling P, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021;23(8):1231\u201351.","journal-title":"Neuro Oncol"},{"issue":"5","key":"3905_CR2","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1016\/S1470-2045(09)70025-7","volume":"10","author":"R Stupp","year":"2009","unstructured":"Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma. Lancet Oncol. 2009;10(5):459\u201366.","journal-title":"Lancet Oncol"},{"issue":"4","key":"3905_CR3","first-page":"299","volume":"70","author":"AC Tan","year":"2020","unstructured":"Tan AC, Ashley DM, L\u00f3pez GY, et al. Management of glioblastoma: State of the art and future directions. CA Cancer J Clin. 2020;70(4):299\u2013312.","journal-title":"CA Cancer J Clin"},{"issue":"8","key":"3905_CR4","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1093\/neuonc\/noaa106","volume":"22","author":"PY Wen","year":"2020","unstructured":"Wen PY, Weller M, Lee EQ, et al. Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and EANO consensus review on current management and future directions. Neuro Oncol. 2020;22(8):1073\u2013113.","journal-title":"Neuro Oncol"},{"issue":"3","key":"3905_CR5","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1038\/s41571-020-00447-z","volume":"18","author":"M Weller","year":"2021","unstructured":"Weller M, van den Bent M, Preusser M, et al. EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nat Rev Clin Oncol. 2021;18(3):170\u201386.","journal-title":"Nat Rev Clin Oncol"},{"issue":"11\u201312","key":"3905_CR6","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1101\/gad.324301.119","volume":"33","author":"RC Gimple","year":"2019","unstructured":"Gimple RC, Bhargava S, Dixit D, Rich JN. Glioblastoma stem cells: lessons from the tumor hierarchy in a lethal cancer. Genes Dev. 2019;33(11\u201312):591\u2013609.","journal-title":"Genes Dev"},{"issue":"7","key":"3905_CR7","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1038\/s41571-018-0003-5","volume":"15","author":"M Lim","year":"2018","unstructured":"Lim M, Xia Y, Bettegowda C, Weller M. Current state of immunotherapy for glioblastoma. Nat Rev Clin Oncol. 2018;15(7):422\u201342.","journal-title":"Nat Rev Clin Oncol"},{"issue":"1","key":"3905_CR8","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1007\/s11060-020-03448-1","volume":"151","author":"R Medikonda","year":"2021","unstructured":"Medikonda R, Dunn G, Rahman M, Fecci P, Lim M. A review of glioblastoma immunotherapy. J Neurooncol. 2021;151(1):41\u201353.","journal-title":"J Neurooncol"},{"issue":"4","key":"3905_CR9","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1016\/j.cell.2019.06.024","volume":"178","author":"C Neftel","year":"2019","unstructured":"Neftel C, Laffy J, Filbin MG, et al. An integrative model of cellular states, plasticity, and genetics for glioblastoma. Cell. 2019;178(4):835\u2013e84921.","journal-title":"Cell"},{"key":"3905_CR10","doi-asserted-by":"publisher","first-page":"1787","DOI":"10.1038\/s41467-019-09853-z","volume":"10","author":"A Dirkse","year":"2019","unstructured":"Dirkse A, Golebiewska A, Buder T, et al. Stem cell-associated heterogeneity in glioblastoma results from intrinsic tumor plasticity shaped by the microenvironment. Nat Commun. 2019;10:1787.","journal-title":"Nat Commun"},{"issue":"1","key":"3905_CR11","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.stem.2019.11.015","volume":"26","author":"A Bhaduri","year":"2020","unstructured":"Bhaduri A, Di Lullo E, Jung D, et al. Outer radial glia-like cancer stem cells contribute to heterogeneity of glioblastoma. Cell Stem Cell. 2020;26(1):48\u2013e636.","journal-title":"Cell Stem Cell"},{"issue":"7412","key":"3905_CR12","doi-asserted-by":"publisher","first-page":"522","DOI":"10.1038\/nature11287","volume":"488","author":"J Chen","year":"2012","unstructured":"Chen J, Li Y, Yu TS, et al. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature. 2012;488(7412):522\u20136.","journal-title":"Nature"},{"issue":"12","key":"3905_CR13","doi-asserted-by":"publisher","first-page":"1203","DOI":"10.1101\/gad.261982.115","volume":"29","author":"JD Lathia","year":"2015","unstructured":"Lathia JD, Mack SC, Mulkearns-Hubert EE, Valentim CLL, Rich JN. Cancer stem cells in glioblastoma. Genes Dev. 2015;29(12):1203\u201317.","journal-title":"Genes Dev"},{"issue":"5","key":"3905_CR14","doi-asserted-by":"publisher","first-page":"630","DOI":"10.1016\/j.ccell.2020.04.001","volume":"37","author":"ML Suv\u00e0","year":"2020","unstructured":"Suv\u00e0 ML, Tirosh I. The glioma stem cell model in the era of single-cell genomics. Cancer Cell. 2020;37(5):630\u20136.","journal-title":"Cancer Cell"},{"issue":"1","key":"3905_CR15","doi-asserted-by":"publisher","first-page":"3406","DOI":"10.1038\/s41467-020-17186-5","volume":"11","author":"CP Couturier","year":"2020","unstructured":"Couturier CP, Ayyadhury S, Le PU, et al. Single-cell RNA-seq reveals that glioblastoma recapitulates a normal neurodevelopmental hierarchy. Nat Commun. 2020;11(1):3406.","journal-title":"Nat Commun"},{"issue":"3","key":"3905_CR16","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1016\/j.ccell.2017.02.009","volume":"31","author":"DF Quail","year":"2017","unstructured":"Quail DF, Joyce JA. The microenvironmental landscape of brain tumors. Cancer Cell. 2017;31(3):326\u201341.","journal-title":"Cancer Cell"},{"issue":"1","key":"3905_CR17","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1038\/nn.4185","volume":"19","author":"D Hambardzumyan","year":"2016","unstructured":"Hambardzumyan D, Gutmann DH, Kettenmann H. The role of microglia and macrophages in glioma maintenance and progression. Nat Neurosci. 2016;19(1):20\u20137.","journal-title":"Nat Neurosci"},{"issue":"7","key":"3905_CR18","doi-asserted-by":"publisher","first-page":"1643","DOI":"10.1016\/j.cell.2020.05.007","volume":"181","author":"F Klemm","year":"2020","unstructured":"Klemm F, Maas RR, Bowman RL, et al. Interrogation of the microenvironmental landscape in brain tumors reveals disease-specific alterations of immune cells. Cell. 2020;181(7):1643\u2013e166017.","journal-title":"Cell"},{"issue":"12","key":"3905_CR19","doi-asserted-by":"publisher","first-page":"786","DOI":"10.1038\/s41568-021-00397-3","volume":"21","author":"BM Andersen","year":"2021","unstructured":"Andersen BM, Faust Akl C, Wheeler MA, et al. Glial and myeloid heterogeneity in the brain tumour microenvironment. Nat Rev Cancer. 2021;21(12):786\u2013802.","journal-title":"Nat Rev Cancer"},{"issue":"6","key":"3905_CR20","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1016\/j.ccell.2021.05.002","volume":"39","author":"T Hara","year":"2021","unstructured":"Hara T, Chanoch-Myers R, Mathewson ND, et al. Interactions between cancer cells and immune cells drive transitions to mesenchymal-like states in glioblastoma. Cancer Cell. 2021;39(6):779\u2013e79211.","journal-title":"Cancer Cell"},{"key":"3905_CR21","doi-asserted-by":"publisher","first-page":"8239258","DOI":"10.1155\/2016\/8239258","volume":"2016","author":"MA Sugimoto","year":"2016","unstructured":"Sugimoto MA, Vago JP, Teixeira MM, Sousa LP. Annexin A1 and the resolution of inflammation: modulation of neutrophil recruitment, apoptosis, and clearance. J Immunol Res. 2016;2016:8239258.","journal-title":"J Immunol Res"},{"issue":"4","key":"3905_CR22","doi-asserted-by":"publisher","first-page":"968","DOI":"10.1096\/fj.06-7464rev","volume":"21","author":"LH Lim","year":"2007","unstructured":"Lim LH, Pervaiz S. Annexin 1: the new face of an old molecule. FASEB J. 2007;21(4):968\u201375.","journal-title":"FASEB J"},{"issue":"2","key":"3905_CR23","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1038\/bjp.2008.252","volume":"155","author":"F D\u2019Acquisto","year":"2008","unstructured":"D\u2019Acquisto F, Perretti M, Flower RJ. Annexin-A1: a pivotal regulator of the innate and adaptive immune systems. Br J Pharmacol. 2008;155(2):152\u201369.","journal-title":"Br J Pharmacol"},{"key":"3905_CR24","doi-asserted-by":"publisher","first-page":"17925","DOI":"10.1038\/s41598-017-17622-5","volume":"7","author":"LA Moraes","year":"2017","unstructured":"Moraes LA, Kar S, Foo SL, et al. Annexin-A1 enhances breast cancer growth and migration by promoting alternative macrophage polarization in the tumour microenvironment. Sci Rep. 2017;7:17925.","journal-title":"Sci Rep"},{"issue":"7","key":"3905_CR25","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1093\/neuonc\/now258","volume":"19","author":"N Colwell","year":"2017","unstructured":"Colwell N, Larion M, Giles AJ, et al. Hypoxia in the glioblastoma microenvironment: shaping the phenotype of cancer stem-like cells. Neuro Oncol. 2017;19(7):887\u201396.","journal-title":"Neuro Oncol"},{"issue":"6","key":"3905_CR26","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1016\/j.ccr.2009.03.018","volume":"15","author":"Z Li","year":"2009","unstructured":"Li Z, Bao S, Wu Q, et al. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell. 2009;15(6):501\u201313.","journal-title":"Cancer Cell"},{"issue":"12","key":"3905_CR27","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1016\/j.trecan.2016.10.016","volume":"2","author":"L Schito","year":"2016","unstructured":"Schito L, Semenza GL. Hypoxia-inducible factors: master regulators of cancer progression. Trends Cancer. 2016;2(12):758\u201370.","journal-title":"Trends Cancer"},{"key":"3905_CR28","doi-asserted-by":"publisher","first-page":"83","DOI":"10.2147\/HP.S93413","volume":"3","author":"B Muz","year":"2015","unstructured":"Muz B, de la Puente P, Azab F, Azab AK. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia (Auckl). 2015;3:83\u201392.","journal-title":"Hypoxia (Auckl)"},{"issue":"1","key":"3905_CR29","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1158\/0008-5472.CAN-08-2470","volume":"69","author":"J Chiche","year":"2009","unstructured":"Chiche J, Ilc K, Laferri\u00e8re J, et al. Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of intracellular pH. Cancer Res. 2009;69(1):358\u201368.","journal-title":"Cancer Res"},{"issue":"1","key":"3905_CR30","doi-asserted-by":"publisher","first-page":"19","DOI":"10.3390\/metabo8010019","volume":"8","author":"MY Mboge","year":"2018","unstructured":"Mboge MY, Mahon BP, McKenna R, Frost SC. Carbonic anhydrases: role in pH control and cancer. Metabolites. 2018;8(1):19.","journal-title":"Metabolites"},{"key":"3905_CR31","doi-asserted-by":"publisher","first-page":"400","DOI":"10.3389\/fphys.2013.00400","volume":"4","author":"O Sedlakova","year":"2014","unstructured":"Sedlakova O, Svastova E, Takacova M, et al. Carbonic anhydrase IX, a hypoxia-induced catalytic component of the pH-regulating machinery in tumors. Front Physiol. 2014;4:400.","journal-title":"Front Physiol"},{"issue":"44","key":"3905_CR32","doi-asserted-by":"publisher","first-page":"5210","DOI":"10.1038\/onc.2012.550","volume":"32","author":"FE Lock","year":"2013","unstructured":"Lock FE, McDonald PC, Lou Y, et al. Targeting carbonic anhydrase IX depletes breast cancer stem cells within the hypoxic niche. Oncogene. 2013;32(44):5210\u20139.","journal-title":"Oncogene"},{"issue":"2","key":"3905_CR33","doi-asserted-by":"publisher","first-page":"25","DOI":"10.3390\/metabo8020025","volume":"8","author":"CT Supuran","year":"2018","unstructured":"Supuran CT. Carbonic anhydrases and metabolism. Metabolites. 2018;8(2):25.","journal-title":"Metabolites"},{"issue":"6","key":"3905_CR34","doi-asserted-by":"publisher","first-page":"1616","DOI":"10.3390\/cancers12061616","volume":"12","author":"SH Lee","year":"2020","unstructured":"Lee SH, Griffiths JR. How and why are cancers acidic? Carbonic anhydrase IX and the homeostatic control of tumour extracellular pH. Cancers (Basel). 2020;12(6):1616.","journal-title":"Cancers (Basel)"},{"issue":"1\u20132","key":"3905_CR35","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1007\/s10555-019-09799-0","volume":"38","author":"S Pastorekova","year":"2019","unstructured":"Pastorekova S, Gillies RJ. The role of carbonic anhydrase IX in cancer development: links to hypoxia, acidosis, and beyond. Cancer Metastasis Rev. 2019;38(1\u20132):65\u201377.","journal-title":"Cancer Metastasis Rev"},{"issue":"14","key":"3905_CR36","doi-asserted-by":"crossref","first-page":"3470","DOI":"10.3390\/cancers14143470","volume":"14","author":"MY Mboge","year":"2022","unstructured":"Mboge MY, Chen Z, Wolff A, et al. Cancer-associated carbonic anhydrases: prognostic biomarkers and therapeutic targets. Cancers (Basel). 2022;14(14):3470.","journal-title":"Cancers (Basel)"},{"issue":"6190","key":"3905_CR37","doi-asserted-by":"publisher","first-page":"1396","DOI":"10.1126\/science.1254257","volume":"344","author":"AP Patel","year":"2014","unstructured":"Patel AP, Tirosh I, Trombetta JJ, et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science. 2014;344(6190):1396\u2013401.","journal-title":"Science"},{"issue":"2","key":"3905_CR38","first-page":"337","volume":"41","author":"Q Wang","year":"2023","unstructured":"Wang Q, Hu B, Hu X, et al. Tumor evolution of glioma-intrinsic gene expression subtype associates with immunological changes in the microenvironment. Cancer Cell. 2023;41(2):337\u2013e3547.","journal-title":"Cancer Cell"},{"issue":"13","key":"3905_CR39","doi-asserted-by":"publisher","first-page":"3573","DOI":"10.1016\/j.cell.2021.04.048","volume":"184","author":"Y Hao","year":"2021","unstructured":"Hao Y, Hao S, Andersen-Nissen E, et al. Integrated analysis of multimodal single-cell data. Cell. 2021;184(13):3573\u2013e358729.","journal-title":"Cell"},{"issue":"1","key":"3905_CR40","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1186\/s13059-019-1874-1","volume":"20","author":"C Hafemeister","year":"2019","unstructured":"Hafemeister C, Satija R. Normalization and variance stabilization of single-cell RNA-seq data using regularized negative binomial regression. Genome Biol. 2019;20(1):296.","journal-title":"Genome Biol"},{"issue":"2","key":"3905_CR41","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1038\/s41590-018-0276-y","volume":"20","author":"D Aran","year":"2019","unstructured":"Aran D, Looney AP, Liu L, et al. Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage. Nat Immunol. 2019;20(2):163\u201372.","journal-title":"Nat Immunol"},{"key":"3905_CR42","unstructured":"Tickle T, Georgescu C, Brown M, Haas B. inferCNV of the Trinity CTAT Project. Broad Institute of MIT and Harvard. Updated 2019. https:\/\/github.com\/broadinstitute\/inferCNV.\u00a0Accessed [ 20 May 2025]"},{"issue":"10","key":"3905_CR43","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1038\/nmeth.4402","volume":"14","author":"X Qiu","year":"2017","unstructured":"Qiu X, Mao Q, Tang Y, et al. Reversed graph embedding resolves complex single-cell trajectories. Nat Methods. 2017;14(10):979\u201382.","journal-title":"Nat Methods"},{"issue":"6476","key":"3905_CR44","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1126\/science.aax0249","volume":"367","author":"GS Gulati","year":"2020","unstructured":"Gulati GS, Sikandar SS, Wesche DJ, et al. Single-cell transcriptional diversity is a hallmark of developmental potential. Science. 2020;367(6476):405\u201311.","journal-title":"Science"},{"issue":"1","key":"3905_CR45","doi-asserted-by":"publisher","first-page":"1088","DOI":"10.1038\/s41467-021-21246-9","volume":"12","author":"S Jin","year":"2021","unstructured":"Jin S, Guerrero-Juarez CF, Zhang L, et al. Inference and analysis of cell-cell communication using CellChat. Nat Commun. 2021;12(1):1088.","journal-title":"Nat Commun"},{"issue":"1","key":"3905_CR46","doi-asserted-by":"publisher","first-page":"e8","DOI":"10.5301\/jbm.5000046","volume":"29","author":"R Biaoxue","year":"2014","unstructured":"Biaoxue R, Xiguang C, Hua L, et al. ANXA1 in malignant tumors: current opinions and controversies. Int J Biol Markers. 2014;29(1):e8\u201320.","journal-title":"Int J Biol Markers"},{"issue":"12","key":"3905_CR47","doi-asserted-by":"publisher","first-page":"2820","DOI":"10.1158\/2159-8290.CD-22-0196","volume":"12","author":"L Wu","year":"2022","unstructured":"Wu L, Wu W, Zhang J, et al. Natural Coevolution of Tumor and Immunoenvironment in Glioblastoma. Cancer Discov. 2022;12(12):2820\u201337.","journal-title":"Cancer Discov"},{"key":"3905_CR48","doi-asserted-by":"publisher","first-page":"1004","DOI":"10.3389\/fimmu.2018.01004","volume":"9","author":"Z Chen","year":"2018","unstructured":"Chen Z, Hambardzumyan D. Immune microenvironment in glioblastoma subtypes. Front Immunol. 2018;9:1004.","journal-title":"Front Immunol"},{"issue":"4","key":"3905_CR49","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1038\/s41593-020-00789-y","volume":"24","author":"AR Pombo Antunes","year":"2021","unstructured":"Pombo Antunes AR, Scheyltjens I, Duerinck J, et al. Single-cell profiling of myeloid cells in glioblastoma across species and disease stage reveals macrophage competition and specialization. Nat Neurosci. 2021;24(4):595\u2013610.","journal-title":"Nat Neurosci"}],"container-title":["Journal of Neuroinflammation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12974-026-03905-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12974-026-03905-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12974-026-03905-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T23:58:57Z","timestamp":1789516737000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s12974-026-03905-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,29]]},"references-count":49,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["3905"],"URL":"https:\/\/doi.org\/10.1186\/s12974-026-03905-0","relation":{},"ISSN":["1742-2094"],"issn-type":[{"value":"1742-2094","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,29]]},"assertion":[{"value":"7 April 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 June 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 June 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All procedures involving human participants were conducted in accordance with the ethical standards of the institutional research committee and with the Declaration of Helsinki. The study protocol was approved by the Institutional Review Board of Union Hospital, Fujian Medical University (approval no. 2023kjcx034). Written informed consent was obtained from all patients or their legal guardians before enrollment. This study was registered in the Chinese Clinical Trial Registry (ChiCTR2200055915).All animal procedures were approved by the Institutional Animal Care and Use Committee of Fujian Medical University (approval no. IACUC FJMU 2022\u2009\u2212\u20090559) and carried out in accordance with institutional guidelines and the Guide for the Care and Use of Laboratory Animals.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Written informed consent for publication was obtained from all participants or their legal guardians.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"315"}}