{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T04:57:43Z","timestamp":1781672263490,"version":"3.54.5"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013069","name":"Leading Talents Program of Guangdong Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013069","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Tumor-associated macrophages (TAMs) are a major immune component of the glioblastoma microenvironment, but macrophage-oriented transcriptomic stratification remains difficult to reproduce across datasets and to validate at the tissue level.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      TCGA-GBM was used as the discovery cohort, and two independent CGGA cohorts (CGGA_693 and CGGA_325) were used for external validation. A continuous transcriptome-defined TAM score was constructed\n                      <jats:italic>a priori<\/jats:italic>\n                      as the mean log-scale expression of five macrophage-associated genes: CD163, MSR1, MRC1, CSF1R, and SPP1. Cohort-specific median dichotomization was used as a secondary categorical representation for visualization and group-level analyses. Differential expression, marker-level characterization, survival analysis, continuous-score sensitivity analyses, external immune benchmark analyses, and negative-control analyses were performed. Local histopathological correlation was assessed in a glioblastoma cohort from the Sichuan Cancer Hospital using immunohistochemistry and digital pathology for CD163, CD68, CD8, and CAIX.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In TCGA, the TAM-rich phenotype was associated with broad upregulation of macrophage- and myeloid-related genes. Across TCGA, CGGA_693, and CGGA_325, macrophage-associated markers, including CD163, MSR1, MRC1, CSF1R, SPP1, VSIG4, MARCO, and TREM1, were consistently increased, and the hypoxia-associated marker CA9 was also elevated. By contrast, CD8A, CXCL9, and CXCL10 showed only modest concordant increases. External immune benchmark analyses using xCell macrophage-related scores and published no-TAM5 macrophage\/TAM signatures supported concordance with macrophage-related immune context, and random-panel and label-permutation analyses reduced concern that the associations reflected arbitrary five-gene scoring or random grouping. Survival association was modest and cohort-dependent. In the local cohort, CD163-defined macrophage-enriched tumors showed higher CD163-positive and CD68-positive macrophage density, greater CAIX-positive area, and a lower CD8\/CD163 ratio, reflecting relative macrophage dominance rather than absolute loss of CD8-positive cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>A compact transcriptome-defined TAM-rich phenotype captures a biologically reproducible, macrophage-enriched and hypoxia-linked immune contexture in glioblastoma. It should be interpreted primarily as a quantitative immune-state classifier and tissue-correlated biological stratifier, rather than as a uniformly independent prognostic factor.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1871268","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T04:50:10Z","timestamp":1781671810000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A transcriptome-defined TAM-rich phenotype identifies a macrophage-enriched, hypoxia-linked immune contexture in glioblastoma: multi-cohort transcriptomic validation and local histopathological correlation"],"prefix":"10.3389","volume":"17","author":[{"given":"Guanpeng","family":"Li","sequence":"first","affiliation":[{"name":"School of Public Health and Emergency Management, Southern University of Science and Technology","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohao","family":"Yan","sequence":"additional","affiliation":[{"name":"Sichuan Cancer Hospital","place":["Chengdu, China"]},{"name":"Chengdu Huake Biological Research Center","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shenying","family":"Fang","sequence":"additional","affiliation":[{"name":"School of Public Health and Emergency Management, Southern University of Science and Technology","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noab106","article-title":"The 2021 WHO classification of tumors of the central nervous system: a summary","volume":"23","author":"Louis","year":"2021","journal-title":"Neuro-oncology"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa043330","article-title":"Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma","volume":"352","author":"Stupp","year":"2005","journal-title":"N Engl J Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/s1470-2045(09)70025-7","article-title":"Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial","volume":"10","author":"Stupp","year":"2009","journal-title":"Lancet Oncol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noaa106","article-title":"Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and\u00a0future directions","volume":"22","author":"Wen","year":"2020","journal-title":"Neuro-oncology"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.5306\/wjco.v14.i4.138","article-title":"Immunotherapy in glioblastoma treatment: current state and future prospects","volume":"14","author":"Rocha Pinheiro","year":"2023","journal-title":"World J Clin Oncol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-024-01226-x","article-title":"Immunotherapy for glioblastoma: current state, challenges, and future perspectives","volume":"21","author":"Liu","year":"2024","journal-title":"Cell Mol Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/aww355","article-title":"Glioblastoma-associated microglia and macrophages: targets for therapies to improve prognosis","volume":"140","author":"Poon","year":"2017","journal-title":"Brain: A J Neurol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"18","DOI":"10.3390\/cells10010018","article-title":"Myeloid cells in glioblastoma microenvironment","volume":"10","author":"De Leo","year":"2020","journal-title":"Cells"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1172\/jci163446","article-title":"Macrophages and microglia in glioblastoma: heterogeneity, plasticity, and therapy","volume":"133","author":"Khan","year":"2023","journal-title":"J Clin Invest"},{"key":"B10","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1186\/s40478-021-01156-z","article-title":"Macrophages and microglia: the cerberus of glioblastoma","volume":"9","author":"Buonfiglioli","year":"2021","journal-title":"Acta Neuropathol Commun"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.887781","article-title":"The role of myeloid cells in GBM immunosuppression","volume":"13","author":"Lin","year":"2022","journal-title":"Front Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0116644","article-title":"Glioma-associated microglia\/macrophages display an expression profile different from M1 and M2 polarization and highly express Gpnmb and Spp1","volume":"10","author":"Szulzewsky","year":"2015","journal-title":"PloS One"},{"key":"B13","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1186\/s13059-017-1362-4","article-title":"Single-cell profiling of human gliomas reveals macrophage ontogeny as a basis for regional differences in macrophage activation in the tumor microenvironment","volume":"18","author":"M\u00fcller","year":"2017","journal-title":"Genome Biol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"19542","DOI":"10.1038\/s41598-020-76657-3","article-title":"Distinct regional ontogeny and activation of tumor associated macrophages in human glioblastoma","volume":"10","author":"Landry","year":"2020","journal-title":"Sci Rep"},{"key":"B15","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1186\/s13073-021-00906-x","article-title":"Single-cell characterization of macrophages in glioblastoma reveals MARCO as a mesenchymal pro-tumor marker","volume":"13","author":"Chen","year":"2021","journal-title":"Genome Med"},{"key":"B16","doi-asserted-by":"publisher","first-page":"20874","DOI":"10.1038\/s41598-023-48116-2","article-title":"Single-cell analysis reveals diversity of tumor-associated macrophages and their interactions with T lymphocytes in glioblastoma","volume":"13","author":"Batchu","year":"2023","journal-title":"Sci Rep"},{"key":"B17","doi-asserted-by":"publisher","first-page":"5775","DOI":"10.3390\/ijms22115775","article-title":"Macrophages\/microglia in the glioblastoma tumor microenvironment","volume":"22","author":"Ma","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3390\/ijms222212608","article-title":"Hypoxia: the cornerstone of glioblastoma","volume":"22","author":"Dom\u00e8nech","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1176","DOI":"10.3390\/cancers14051176","article-title":"Current understanding of hypoxia in glioblastoma multiforme and its response to immunotherapy","volume":"14","author":"Park","year":"2022","journal-title":"Cancers"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3892\/or.2016.5171","article-title":"Hypoxia and macrophages promote glioblastoma invasion by the CCL4-CCR5 axis","volume":"36","author":"Wang","year":"2016","journal-title":"Oncol Rep"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1384249","article-title":"Hypoxia within the glioblastoma tumor microenvironment: a master saboteur of novel treatments","volume":"15","author":"Feldman","year":"2024","journal-title":"Front Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/nos216","article-title":"Function of carbonic anhydrase IX in glioblastoma multiforme","volume":"14","author":"Proescholdt","year":"2012","journal-title":"Neuro-oncology"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noz117","article-title":"Targeting hypoxia downstream signaling protein, CAIX, for CAR T-cell therapy against glioblastoma","volume":"21","author":"Cui","year":"2019","journal-title":"Neuro-oncology"},{"key":"B24","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1016\/j.cell.2019.06.024","article-title":"An integrative model of cellular states, plasticity, and genetics for glioblastoma","volume":"178","author":"Neftel","year":"2019","journal-title":"Cell"},{"key":"B25","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1016\/j.ccell.2021.05.002","article-title":"Interactions between cancer cells and immune cells drive transitions to mesenchymal-like states in glioblastoma","volume":"39","author":"Hara","year":"2021","journal-title":"Cancer Cell"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2022.12.008","article-title":"T cell exhaustion in Malignant gliomas","volume":"9","author":"Watowich","year":"2023","journal-title":"Trends Cancer"},{"key":"B27","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1186\/s40425-019-0536-x","article-title":"The immune suppressive microenvironment of human gliomas depends on the accumulation of bone marrow-derived macrophages in the center of the lesion","volume":"7","author":"Pinton","year":"2019","journal-title":"J Immunother Cancer"},{"key":"B28","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1038\/s41467-022-28523-1","article-title":"T-cell dysfunction in the glioblastoma microenvironment is mediated by myeloid cells releasing interleukin-10","volume":"13","author":"Ravi","year":"2022","journal-title":"Nat Commun"},{"key":"B29","doi-asserted-by":"publisher","first-page":"846","DOI":"10.3390\/biology13100846","article-title":"Role of T lymphocytes in glioma immune microenvironment: two sides of a coin","volume":"13","author":"Noor","year":"2024","journal-title":"Biology"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1080\/2162402x.2019.1601478","article-title":"Molecular and clinical characterization of CD163 expression via large-scale analysis in glioma","volume":"8","author":"Liu","year":"2019","journal-title":"Oncoimmunology"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3337","article-title":"CSF-1R inhibition alters macrophage polarization and blocks glioma progression","volume":"19","author":"Pyonteck","year":"2013","journal-title":"Nat Med"},{"key":"B32","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1186\/s13578-024-01218-4","article-title":"Revealing the role of SPP1(+) macrophages in glioma prognosis and therapeutic targeting by investigating tumor-associated macrophage landscape in grade 2 and 3 gliomas","volume":"14","author":"Tang","year":"2024","journal-title":"Cell Biosci"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1080\/2162402x.2024.2425124","article-title":"Markers of tumor-associated macrophages and microglia exhibit high intratumoral heterogeneity in human glioblastoma tissue","volume":"13","author":"Ispirjan","year":"2024","journal-title":"Oncoimmunology"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.585616","article-title":"Glioblastoma immune landscape and the potential of new immunotherapies","volume":"11","author":"Daubon","year":"2020","journal-title":"Front Immunol"},{"key":"B35","doi-asserted-by":"publisher","first-page":"Article3","DOI":"10.2202\/1544-6115.1027","article-title":"Linear models and empirical bayes methods for assessing differential expression in microarray experiments","volume":"3","author":"Smyth","year":"2004","journal-title":"Stat Appl Genet Mol Biol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/1471-2105-14-7","article-title":"GSVA: gene set variation analysis for microarray and RNA-seq data","volume":"14","author":"H\u00e4nzelmann","year":"2013","journal-title":"BMC Bioinf"},{"key":"B37","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1186\/s13059-017-1349-1","article-title":"xCell: digitally portraying the tissue cellular heterogeneity landscape","volume":"18","author":"Aran","year":"2017","journal-title":"Genome Biol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2024.217007","article-title":"PDP1 promotes KRAS mutant colorectal cancer progression by serving as a scaffold for BRAF and MEK1","volume":"597","author":"Yuan","year":"2024","journal-title":"Cancer Lett"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202500461","article-title":"ACSS2-mediated histone H4 lysine 12 crotonylation (H4K12cr) alleviates colitis via enhancing transcription of CLDN7","volume":"12","author":"Yuan","year":"2025","journal-title":"Adv Sci Weinheim Baden-Wurttemberg Germany"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2025.101558","article-title":"Exercise-induced metabolite N-lactoyl-phenylalanine ameliorates colitis by inhibiting M1 macrophage polarization via the suppression of the NF-\u03baB signaling pathway","volume":"19","author":"Yu","year":"2025","journal-title":"Cell Mol Gastroenterol Hepatol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2025.114579","article-title":"NCOA3 impairs the efficacy of anti-PD-L1 therapy via HSP90\u03b1\/EZH2\/CXCL9 axis in colon cancer","volume":"155","author":"Liu","year":"2025","journal-title":"Int Immunopharmacol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1002\/1878-0261.13657","article-title":"Microglia and macrophages in glioblastoma: landscapes and treatment directions","volume":"18","author":"Solomou","year":"2024","journal-title":"Mol Oncol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1871268\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T04:50:28Z","timestamp":1781671828000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1871268\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,17]]},"references-count":42,"alternative-id":["10.3389\/fimmu.2026.1871268"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1871268","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,17]]},"article-number":"1871268"}}