{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:36:56Z","timestamp":1792791416471,"version":"4.5.0"},"reference-count":94,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,5,7]],"date-time":"2024-05-07T00:00:00Z","timestamp":1715040000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>The current median survival for glioblastoma (GBM) patients is only about 16 months, with many patients succumbing to the disease in just a matter of months, making it the most common and aggressive primary brain cancer in adults. This poor outcome is, in part, due to the lack of new treatment options with only one FDA-approved treatment in the last decade. Advances in sequencing techniques and transcriptomic analyses have revealed a vast degree of heterogeneity in GBM, from inter-patient diversity to intra-tumoral cellular variability. These cutting-edge approaches are providing new molecular insights highlighting a critical role for the tumor microenvironment (TME) as a driver of cellular plasticity and phenotypic heterogeneity. With this expanded molecular toolbox, the influence of TME factors, including endogenous (e.g., oxygen and nutrient availability and interactions with non-malignant cells) and iatrogenically induced (e.g., post-therapeutic intervention) stimuli, on tumor cell states can be explored to a greater depth. There exists a critical need for interrogating the temporal and spatial aspects of patient tumors at a high, cell-level resolution to identify therapeutically targetable states, interactions and mechanisms. In this review, we discuss advancements in our understanding of spatiotemporal diversity in GBM with an emphasis on the influence of hypoxia and immune cell interactions on tumor cell heterogeneity. Additionally, we describe specific high-resolution spatially resolved methodologies and their potential to expand the impact of pre-clinical GBM studies. Finally, we highlight clinical attempts at targeting hypoxia- and immune-related mechanisms of malignancy and the potential therapeutic opportunities afforded by single-cell and spatial exploration of GBM patient specimens.<\/jats:p>","DOI":"10.3389\/fgene.2024.1356611","type":"journal-article","created":{"date-parts":[[2024,5,7]],"date-time":"2024-05-07T04:32:08Z","timestamp":1715056328000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Cellular diversity through space and time: adding new dimensions to GBM therapeutic development"],"prefix":"10.3389","volume":"15","author":[{"given":"Amanda L.","family":"Johnson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hernando","family":"Lopez-Bertoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,5,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2586","DOI":"10.1038\/s41467-023-38186-1","article-title":"Re-convolving the compositional landscape of primary and recurrent glioblastoma reveals prognostic and targetable tissue states","volume":"14","author":"Al-Dalahmah","year":"2023","journal-title":"Nat. Commun."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/13543776.2021.1954617","article-title":"Hypoxia-activated prodrug derivatives of anti-cancer drugs: a patent review 2006 - 2021","volume":"32","author":"Anduran","year":"2022","journal-title":"Expert Opin. Ther. Pat."},{"key":"B3","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.stem.2019.11.015","article-title":"Outer radial glia-like cancer stem cells contribute to heterogeneity of glioblastoma","volume":"26","author":"Bhaduri","year":"2020","journal-title":"Cell Stem Cell"},{"key":"B4","doi-asserted-by":"publisher","first-page":"2306","DOI":"10.1038\/s41598-021-81841-0","article-title":"Phase 2 trial of hypoxia activated evofosfamide (Th302) for treatment of recurrent bevacizumab-refractory glioblastoma","volume":"11","author":"Brenner","year":"2021","journal-title":"Sci. Rep."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1469","DOI":"10.1038\/s41588-021-00927-7","article-title":"Epigenetic encoding, heritability and plasticity of glioma transcriptional cell states","volume":"53","author":"Chaligne","year":"2021","journal-title":"Nat. Genet."},{"key":"B6","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1186\/s13073-022-01109-8","article-title":"Elucidating the diversity of malignant mesenchymal states in glioblastoma by integrative analysis","volume":"14","author":"Chanoch-Myers","year":"2022","journal-title":"Genome Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1777","DOI":"10.1016\/j.cell.2022.04.003","article-title":"Spatiotemporal transcriptomic Atlas of mouse organogenesis using DNA nanoball-patterned arrays","volume":"185","author":"Chen","year":"","journal-title":"Cell"},{"key":"B8","doi-asserted-by":"publisher","first-page":"166534","DOI":"10.1016\/j.bbadis.2022.166534","article-title":"Single-cell rna sequencing reveals intra-tumoral heterogeneity of glioblastoma and a pro-tumor subset of tumor-associated macrophages characterized by Ezh2 overexpression","volume":"1868","author":"Chen","year":"","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"B9","doi-asserted-by":"publisher","first-page":"3559","DOI":"10.1016\/j.cell.2021.05.010","article-title":"Microscopic examination of spatial transcriptome using seq-scope","volume":"184","author":"Cho","year":"2021","journal-title":"Cell"},{"key":"B10","first-page":"837","article-title":"In vitro evaluation of adenosine 5'-monophosphate as an imaging agent of tumor metabolism","volume":"47","author":"Cho","year":"2006","journal-title":"J. Nucl. Med."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1111","DOI":"10.1016\/j.ccell.2022.08.014","article-title":"Cancer cell autophagy, reprogrammed macrophages, and remodeled vasculature in glioblastoma triggers tumor immunity","volume":"40","author":"Chryplewicz","year":"2022","journal-title":"Cancer Cell"},{"key":"B12","doi-asserted-by":"publisher","first-page":"3406","DOI":"10.1038\/s41467-020-17186-5","article-title":"Single-cell rna-seq reveals that glioblastoma recapitulates a normal neurodevelopmental hierarchy","volume":"11","author":"Couturier","year":"2020","journal-title":"Nat. Commun."},{"key":"B13","doi-asserted-by":"publisher","first-page":"4814","DOI":"10.1038\/s41467-022-32430-w","article-title":"Single cell spatial analysis reveals the topology of immunomodulatory purinergic signaling in glioblastoma","volume":"13","author":"Coy","year":"2022","journal-title":"Nat. Commun."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1787","DOI":"10.1038\/s41467-019-09853-z","article-title":"Stem cell-associated heterogeneity in glioblastoma results from intrinsic tumor plasticity shaped by the microenvironment","volume":"10","author":"Dirkse","year":"2019","journal-title":"Nat. Commun."},{"key":"B15","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1186\/s13059-021-02286-2","article-title":"Giotto: a toolbox for integrative analysis and visualization of spatial expression data","volume":"22","author":"Dries","year":"2021","journal-title":"Genome Biol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"6665","DOI":"10.1038\/s41467-022-34208-6","article-title":"Spatial analysis of the glioblastoma proteome reveals specific molecular signatures and markers of survival","volume":"13","author":"Duhamel","year":"2022","journal-title":"Nat. Commun."},{"key":"B17","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1038\/s41586-019-1049-y","article-title":"Transcriptome-scale super-resolved imaging in tissues by rna seqfish","volume":"568","author":"Eng","year":"2019","journal-title":"Nature"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1626","DOI":"10.1016\/j.cell.2020.04.055","article-title":"Single-cell mapping of human brain cancer reveals tumor-specific instruction of tissue-invading leukocytes","volume":"181","author":"Friebel","year":"2020","journal-title":"Cell"},{"key":"B19","doi-asserted-by":"publisher","first-page":"560211","DOI":"10.3389\/fonc.2020.560211","article-title":"Cytof analysis reveals a distinct immunosuppressive microenvironment in idh mutant anaplastic gliomas","volume":"10","author":"Fu","year":"2020","journal-title":"Front. Oncol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1038\/s43018-020-00159-4","article-title":"Pathway-based classification of glioblastoma uncovers a mitochondrial subtype with therapeutic vulnerabilities","volume":"2","author":"Garofano","year":"2021","journal-title":"Nat. Cancer"},{"key":"B21","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1038\/nmeth.2869","article-title":"Highly multiplexed imaging of tumor tissues with subcellular resolution by mass cytometry","volume":"11","author":"Giesen","year":"2014","journal-title":"Nat. Methods"},{"key":"B22","doi-asserted-by":"publisher","first-page":"968","DOI":"10.1016\/j.cell.2018.07.010","article-title":"Deep profiling of mouse splenic architecture with codex multiplexed imaging","volume":"174","author":"Goltsev","year":"2018","journal-title":"Cell"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1455","DOI":"10.1038\/s43018-023-00620-0","article-title":"Myeloid-specific Kdm6b inhibition sensitizes glioblastoma to Pd1 blockade","volume":"4","author":"Goswami","year":"2023","journal-title":"Nat. Cancer"},{"key":"B24","doi-asserted-by":"publisher","first-page":"e64090","DOI":"10.7554\/eLife.64090","article-title":"Single-cell chromatin accessibility profiling of glioblastoma identifies an invasive cancer stem cell population associated with lower survival","volume":"10","author":"Guilhamon","year":"2021","journal-title":"Elife"},{"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","first-page":"1794","DOI":"10.1038\/s41587-022-01483-z","article-title":"High-plex imaging of rna and proteins at subcellular resolution in fixed tissue by spatial molecular imaging","volume":"40","author":"He","year":"2022","journal-title":"Nat. Biotechnol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"3050","DOI":"10.1158\/1078-0432.CCR-20-4118","article-title":"A phase I dose-escalation study to evaluate the safety and tolerability of evofosfamide in combination with ipilimumab in advanced solid malignancies","volume":"27","author":"Hegde","year":"2021","journal-title":"Clin. Cancer Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1016\/j.cell.2015.08.012","article-title":"Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses","volume":"162","author":"Ho","year":"2015","journal-title":"Cell"},{"key":"B29","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1016\/j.ccell.2023.02.019","article-title":"Transcriptome analysis reveals tumor microenvironment changes in glioblastoma","volume":"41","author":"Hoogstrate","year":"2023","journal-title":"Cancer Cell"},{"key":"B30","doi-asserted-by":"publisher","first-page":"149","DOI":"10.12659\/msm.905372","article-title":"Downregulation of annexin A11 (ANXA11) inhibits cell proliferation, invasion, and migration via the AKT\/GSK-3\u03b2 pathway in gastric cancer","volume":"24","author":"Hua","year":"2018","journal-title":"Med. Sci. Monit."},{"key":"B31","doi-asserted-by":"publisher","first-page":"e147087","DOI":"10.1172\/JCI147087","article-title":"Single-cell rna sequencing and spatial transcriptomics reveal cancer-associated fibroblasts in glioblastoma with protumoral effects","volume":"133","author":"Jain","year":"2023","journal-title":"J. Clin. Invest."},{"key":"B32","doi-asserted-by":"publisher","first-page":"5137","DOI":"10.1172\/JCI96268","article-title":"Targeted hypoxia reduction restores T cell infiltration and sensitizes prostate cancer to immunotherapy","volume":"128","author":"Jayaprakash","year":"2018","journal-title":"J. Clin. Invest."},{"key":"B33","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1080\/10731190903043192","article-title":"In vitro comparison of dodecafluoropentane (ddfp), perfluorodecalin (pfd), and perfluoroctylbromide (pfob) in the facilitation of oxygen exchange","volume":"37","author":"Johnson","year":"2009","journal-title":"Artif. Cells Blood Substit. Immobil. Biotechnol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1456","DOI":"10.1038\/s41588-021-00926-8","article-title":"Single-cell multimodal glioma analyses identify epigenetic regulators of cellular plasticity and environmental stress response","volume":"53","author":"Johnson","year":"2021","journal-title":"Nat. Genet."},{"key":"B35","doi-asserted-by":"publisher","first-page":"vii33","DOI":"10.1093\/neuonc\/noac209.130","article-title":"Stem-13 glioma stem cells mimic regulatory T cell function to suppress the immune response and promote tumor propagation","volume":"24","author":"Johnson Aljk","year":"2022","journal-title":"Neuro Oncol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.canlet.2015.01.010","article-title":"Hypoxia enhances migration and invasion in glioblastoma by promoting a mesenchymal shift mediated by the HIF1\u03b1-ZEB1 axis","volume":"359","author":"Joseph","year":"2015","journal-title":"Cancer Lett."},{"key":"B37","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1038\/s41586-022-05680-3","article-title":"Single-cell spatial immune landscapes of primary and metastatic brain tumours","volume":"614","author":"Karimi","year":"2023","journal-title":"Nature"},{"key":"B38","doi-asserted-by":"publisher","first-page":"100034","DOI":"10.1016\/j.modpat.2022.100034","article-title":"Highly multiplexed spatially resolved proteomic and transcriptional profiling of the glioblastoma microenvironment using archived formalin-fixed paraffin-embedded specimens","volume":"36","author":"Kim","year":"2023","journal-title":"Mod. Pathol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"4870","DOI":"10.1016\/j.csbj.2022.08.043","article-title":"Computational solutions for spatial transcriptomics","volume":"20","author":"Kleino","year":"2022","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"B40","doi-asserted-by":"publisher","first-page":"6938","DOI":"10.1038\/s41467-021-26940-2","article-title":"Neoadjuvant Pd-1 blockade induces T cell and Cdc1 activation but fails to overcome the immunosuppressive tumor associated macrophages in recurrent glioblastoma","volume":"12","author":"Lee","year":"2021","journal-title":"Nat. Commun."},{"key":"B41","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1038\/nprot.2014.191","article-title":"Fluorescent in situ sequencing (fisseq) of rna for gene expression profiling in intact cells and tissues","volume":"10","author":"Lee","year":"2015","journal-title":"Nat. Protoc."},{"key":"B42","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1016\/j.stem.2016.11.003","article-title":"Adaptive chromatin remodeling drives glioblastoma stem cell plasticity and drug tolerance","volume":"20","author":"Liau","year":"2017","journal-title":"Cell Stem Cell"},{"key":"B43","doi-asserted-by":"publisher","first-page":"1607","DOI":"10.1158\/2767-9764.CRC-22-0433","article-title":"Dodecafluoropentane emulsion as a radiosensitizer in glioblastoma multiforme","volume":"3","author":"Lickliter","year":"2023","journal-title":"Cancer Res. Commun."},{"key":"B44","doi-asserted-by":"publisher","first-page":"8390","DOI":"10.1038\/ncomms9390","article-title":"Highly multiplexed imaging of single cells using a high-throughput cyclic immunofluorescence method","volume":"6","author":"Lin","year":"2015","journal-title":"Nat. Commun."},{"key":"B45","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.biopha.2015.01.011","article-title":"Annexin A11 knockdown inhibits in vitro proliferation and enhances survival of hca-F cell via akt2\/foxo1 pathway and mmp-9 expression","volume":"70","author":"Liu","year":"2015","journal-title":"Biomed. Pharmacother."},{"key":"B46","doi-asserted-by":"publisher","first-page":"1405","DOI":"10.1038\/s41587-023-01676-0","article-title":"High-plex protein and whole transcriptome Co-mapping at cellular resolution with spatial cite-seq","volume":"41","author":"Liu","year":"2023","journal-title":"Nat. Biotechnol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"1231","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 Oncol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"3256","DOI":"10.3390\/cancers15123256","article-title":"Spatial distribution of immune cells in primary and recurrent glioblastoma: a small case study","volume":"15","author":"Loussouarn","year":"2023","journal-title":"Cancers (Basel)"},{"key":"B49","doi-asserted-by":"publisher","first-page":"2457","DOI":"10.1158\/0008-5472.CAN-20-2489","article-title":"Reprogramming transcription factors Oct4 and Sox2 induce a brd-dependent immunosuppressive transcriptome in gbm-propagating cells","volume":"81","author":"Ma","year":"2021","journal-title":"Cancer Res."},{"key":"B50","doi-asserted-by":"publisher","first-page":"1349","DOI":"10.1038\/s41587-022-01273-7","article-title":"Spatially informed cell-type deconvolution for spatial transcriptomics","volume":"40","author":"Ma","year":"2022","journal-title":"Nat. Biotechnol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1007\/s11060-020-03448-1","article-title":"A review of glioblastoma immunotherapy","volume":"151","author":"Medikonda","year":"2021","journal-title":"J. Neurooncol"},{"key":"B52","doi-asserted-by":"publisher","first-page":"586","DOI":"10.1038\/s41587-020-0472-9","article-title":"Multiplex digital spatial profiling of proteins and rna in fixed tissue","volume":"38","author":"Merritt","year":"2020","journal-title":"Nat. Biotechnol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"vdad142","DOI":"10.1093\/noajnl\/vdad142","article-title":"Spatial architecture of high-grade glioma reveals tumor heterogeneity within distinct domains","volume":"5","author":"Moffet","year":"2023","journal-title":"Neurooncol Adv."},{"key":"B54","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1111\/j.1525-1594.2011.01418.x","article-title":"Liposome-encapsulated hemoglobin ameliorates tumor hypoxia and enhances radiation therapy to suppress tumor growth in mice","volume":"36","author":"Murayama","year":"2012","journal-title":"Artif. Organs"},{"key":"B55","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":"B56","doi-asserted-by":"publisher","first-page":"iv1","DOI":"10.1093\/neuonc\/noad149","article-title":"Cbtrus statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2016-2020","volume":"25","author":"Ostrom","year":"2023","journal-title":"Neuro Oncol."},{"key":"B57","doi-asserted-by":"publisher","first-page":"1396","DOI":"10.1126\/science.1254257","article-title":"Single-cell rna-seq highlights intratumoral heterogeneity in primary glioblastoma","volume":"344","author":"Patel","year":"2014","journal-title":"Science"},{"key":"B58","doi-asserted-by":"publisher","first-page":"7739","DOI":"10.1038\/s41467-023-43120-6","article-title":"Robust mapping of spatiotemporal trajectories and cell-cell interactions in healthy and diseased tissues","volume":"14","author":"Pham","year":"2023","journal-title":"Nat. Commun."},{"key":"B59","doi-asserted-by":"publisher","first-page":"2400","DOI":"10.3390\/cancers13102400","article-title":"Targeting Csf1r alone or in combination with Pd1 in experimental glioma","volume":"13","author":"Przystal","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B60","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1126\/science.aaf2666","article-title":"An anatomic transcriptional Atlas of human glioblastoma","volume":"360","author":"Puchalski","year":"2018","journal-title":"Science"},{"key":"B61","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1016\/j.cmet.2023.11.013","article-title":"Myeloid cell-derived creatine in the hypoxic niche promotes glioblastoma growth","volume":"36","author":"Rashidi","year":"2024","journal-title":"Cell Metab."},{"key":"B62","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":"","journal-title":"Nat. Commun."},{"key":"B63","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1016\/j.ccell.2022.05.009","article-title":"Spatially resolved multi-omics deciphers bidirectional tumor-host interdependence in glioblastoma","volume":"40","author":"Ravi","year":"","journal-title":"Cancer Cell"},{"key":"B64","doi-asserted-by":"publisher","first-page":"1028","DOI":"10.1038\/s41467-023-36707-6","article-title":"Spatial transcriptomics reveals niche-specific enrichment and vulnerabilities of radial glial stem-like cells in malignant gliomas","volume":"14","author":"Ren","year":"2023","journal-title":"Nat. Commun."},{"key":"B65","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1038\/s43018-020-00154-9","article-title":"Gradient of developmental and injury response transcriptional states defines functional vulnerabilities underpinning glioblastoma heterogeneity","volume":"2","author":"Richards","year":"2021","journal-title":"Nat. Cancer"},{"key":"B66","doi-asserted-by":"publisher","first-page":"1825","DOI":"10.1016\/j.immuni.2023.06.017","article-title":"Hypoxic niches attract and sequester tumor-associated macrophages and cytotoxic T cells and reprogram them for immunosuppression","volume":"56","author":"Sattiraju","year":"2023","journal-title":"Immunity"},{"key":"B67","doi-asserted-by":"publisher","first-page":"eabn9440","DOI":"10.1126\/sciadv.abn9440","article-title":"Immunotherapy of glioblastoma explants induces interferon-gamma responses and spatial immune cell rearrangements in tumor center, but not periphery","volume":"8","author":"Shekarian","year":"2022","journal-title":"Sci. Adv."},{"key":"B68","doi-asserted-by":"publisher","first-page":"e002181","DOI":"10.1136\/jitc-2020-002181","article-title":"Deep immune profiling reveals targetable mechanisms of immune evasion in immune checkpoint inhibitor-refractory glioblastoma","volume":"9","author":"Simonds","year":"2021","journal-title":"J. Immunother. Cancer"},{"key":"B69","doi-asserted-by":"publisher","first-page":"2532","DOI":"10.4049\/jimmunol.1502464","article-title":"Suppression of Glut1 and glucose metabolism by decreased akt\/mtorc1 signaling drives T cell impairment in B cell leukemia","volume":"197","author":"Siska","year":"2016","journal-title":"J. Immunol."},{"key":"B70","doi-asserted-by":"publisher","first-page":"4009","DOI":"10.1073\/pnas.1219747110","article-title":"Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics","volume":"110","author":"Sottoriva","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B71","doi-asserted-by":"publisher","first-page":"eade3559","DOI":"10.1126\/sciadv.ade3559","article-title":"Trem2 inhibition triggers antitumor cell activity of myeloid cells in glioblastoma","volume":"9","author":"Sun","year":"2023","journal-title":"Sci. Adv."},{"key":"B72","doi-asserted-by":"publisher","first-page":"872","DOI":"10.1021\/jasms.0c00439","article-title":"Spatially resolved mass spectrometry at the single cell: recent innovations in proteomics and metabolomics","volume":"32","author":"Taylor","year":"2021","journal-title":"J. Am. Soc. Mass Spectrom."},{"key":"B73","first-page":"301","article-title":"Peg-hemoglobin: effects on tumor oxygenation and response to chemotherapy","volume":"11","author":"Teicher","year":"1997","journal-title":"Vivo"},{"key":"B74","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1038\/s43018-023-00547-6","article-title":"Cd103(+) regulatory T cells underlie resistance to radio-immunotherapy and impair Cd8(+) T cell activation in glioblastoma","volume":"4","author":"van Hooren","year":"2023","journal-title":"Nat. Cancer"},{"key":"B75","doi-asserted-by":"publisher","first-page":"2184","DOI":"10.1016\/j.cell.2022.04.038","article-title":"Glioma progression is shaped by genetic evolution and microenvironment interactions","volume":"185","author":"Varn","year":"2022","journal-title":"Cell"},{"key":"B76","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.ccr.2009.12.020","article-title":"Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in pdgfra, Idh1, egfr, and Nf1","volume":"17","author":"Verhaak","year":"2010","journal-title":"Cancer Cell"},{"key":"B77","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1038\/s41592-019-0548-y","article-title":"High-definition spatial transcriptomics for in situ tissue profiling","volume":"16","author":"Vickovic","year":"2019","journal-title":"Nat. Methods"},{"key":"B78","doi-asserted-by":"publisher","first-page":"750675","DOI":"10.3389\/fgene.2021.750675","article-title":"Immunotherapy resistance in glioblastoma","volume":"12","author":"Wang","year":"2021","journal-title":"Front. Genet."},{"key":"B79","doi-asserted-by":"publisher","first-page":"1534","DOI":"10.1038\/s43018-022-00475-x","article-title":"A single-cell Atlas of glioblastoma evolution under therapy reveals cell-intrinsic and cell-extrinsic therapeutic targets","volume":"3","author":"Wang","year":"2022","journal-title":"Nat. Cancer"},{"key":"B80","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.ccell.2017.06.003","article-title":"Tumor evolution of glioma-intrinsic gene expression subtypes associates with immunological changes in the microenvironment","volume":"32","author":"Wang","year":"2017","journal-title":"Cancer Cell"},{"key":"B81","doi-asserted-by":"publisher","first-page":"eaat5691","DOI":"10.1126\/science.aat5691","article-title":"Three-dimensional intact-tissue sequencing of single-cell transcriptional states","volume":"361","author":"Wang","year":"2018","journal-title":"Science"},{"key":"B82","doi-asserted-by":"publisher","first-page":"110671","DOI":"10.1016\/j.ygeno.2023.110671","article-title":"Spatial transcriptomics: technologies, applications and experimental considerations","volume":"115","author":"Wang","year":"","journal-title":"Genomics"},{"key":"B83","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1186\/s12951-023-02203-8","article-title":"Th-302-Loaded nanodrug reshapes the hypoxic tumour microenvironment and enhances Pd-1 blockade efficacy in gastric cancer","volume":"21","author":"Wang","year":"","journal-title":"J. Nanobiotechnology"},{"key":"B84","doi-asserted-by":"publisher","first-page":"1073","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 future directions","volume":"22","author":"Wen","year":"2020","journal-title":"Neuro Oncol."},{"key":"B85","doi-asserted-by":"publisher","first-page":"914236","DOI":"10.3389\/fimmu.2022.914236","article-title":"Single-cell transcriptomics revealed subtype-specific tumor immune microenvironments in human glioblastomas","volume":"13","author":"Xiao","year":"2022","journal-title":"Front. Immunol."},{"key":"B86","doi-asserted-by":"publisher","first-page":"104239","DOI":"10.1016\/j.ebiom.2022.104239","article-title":"Integrated single-cell transcriptomic analyses reveal that gpnmb-high macrophages promote pn-mes transition and impede T cell activation in gbm","volume":"83","author":"Xiong","year":"2022","journal-title":"EBioMedicine"},{"key":"B87","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1093\/neuonc\/noab269","article-title":"Cancer cell heterogeneity and plasticity: a paradigm shift in glioblastoma","volume":"24","author":"Yabo","year":"2022","journal-title":"Neuro Oncol."},{"key":"B88","doi-asserted-by":"publisher","first-page":"444","DOI":"10.4049\/jimmunol.1103248","article-title":"Tumor-associated microglia\/macrophages enhance the invasion of glioma stem-like cells via TGF-\u03b21 signaling pathway","volume":"189","author":"Ye","year":"2012","journal-title":"J. Immunol."},{"key":"B89","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1186\/s13073-018-0567-9","article-title":"Single-cell transcriptome analysis of lineage diversity in high-grade glioma","volume":"10","author":"Yuan","year":"2018","journal-title":"Genome Med."},{"key":"B90","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1186\/s13059-020-02214-w","article-title":"Gcng: graph convolutional networks for inferring gene interaction from spatial transcriptomics data","volume":"21","author":"Yuan","year":"2020","journal-title":"Genome Biol."},{"key":"B91","doi-asserted-by":"publisher","first-page":"e0153550","DOI":"10.1371\/journal.pone.0153550","article-title":"Anti-Cd47 treatment stimulates phagocytosis of glioblastoma by M1 and M2 polarized macrophages and promotes M1 polarized macrophages in vivo","volume":"11","author":"Zhang","year":"2016","journal-title":"PLoS One"},{"key":"B92","doi-asserted-by":"publisher","first-page":"1610","DOI":"10.1038\/s41467-023-37328-9","article-title":"Sting agonist-loaded, Cd47\/Pd-L1-Targeting nanoparticles potentiate antitumor immunity and radiotherapy for glioblastoma","volume":"14","author":"Zhang","year":"2023","journal-title":"Nat. Commun."},{"key":"B93","doi-asserted-by":"publisher","first-page":"4122","DOI":"10.1038\/s41467-023-39933-0","article-title":"Spatial cellular architecture predicts prognosis in glioblastoma","volume":"14","author":"Zheng","year":"2023","journal-title":"Nat. Commun."},{"key":"B94","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1186\/s43556-023-00144-0","article-title":"Spatial transcriptomics in development and disease","volume":"4","author":"Zhou","year":"2023","journal-title":"Mol. Biomed."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2024.1356611\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,7]],"date-time":"2024-05-07T04:32:11Z","timestamp":1715056331000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2024.1356611\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,7]]},"references-count":94,"alternative-id":["10.3389\/fgene.2024.1356611"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2024.1356611","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,7]]},"article-number":"1356611"}}