{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T11:26:41Z","timestamp":1787225201128,"version":"build-2736575974"},"reference-count":203,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Glioblastoma (GBM) recurs predominantly from infiltrative disease that persists beyond the contrast-enhancing tumor (CET). This structured narrative review aims to define the invasive margin and peritumoral brain zone (PBZ) as a spatially organized molecular ecosystem, summarize the approaches used to interrogate this compartment, and evaluate how malignant-cell plasticity, host niches, and treatment-induced remodeling contribute to minimal residual disease and recurrence. A structured literature search of PubMed\/MEDLINE, Scopus, and Web of Science identified the clinical, translational, preclinical, and review literature available through July 2026; evidence was synthesized qualitatively, with priority given to human tissue studies and single-cell or spatially resolved analyses. Across studies, the margin differs from both tumor core and normal brain and contains heterogeneous malignant states interacting with neural, vascular, immune, hypoxic, and extracellular-matrix-supported niches. Surgery, radiotherapy, and systemic treatment further reshape these interactions through inflammation, vascular injury, senescence, hypoxia, and fibrosis. The main translational challenge is therefore not simply to control the CET, but to identify biologically high-risk non-enhancing tissue and demonstrate that therapy reaches and modifies it. We propose three priorities: image-registered characterization of residual compartments, regional measurement of drug exposure and target engagement, and integration of local margin control with distributed and niche-directed treatment. Prospective validation is required before spatial PBZ biomarkers can guide routine care.<\/jats:p>","DOI":"10.3390\/ijms27167449","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T10:55:18Z","timestamp":1787223318000},"page":"7449","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Invasive Margin of Glioblastoma as a Molecular Ecosystem: Spatial Heterogeneity, Tumor\u2013Host Interactions, and Therapeutic Opportunities"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-4905-5086","authenticated-orcid":false,"given":"Nikodem","family":"Kuczy\u0144ski","sequence":"first","affiliation":[{"name":"Faculty of Medicine, Collegium Medicum, The Mazovian University in P\u0142ock, 09-402 P\u0142ock, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7520-9106","authenticated-orcid":false,"given":"Dawid","family":"Larysz","sequence":"additional","affiliation":[{"name":"Department of Head and Neck Surgery for Children and Adolescents, University of Warmia and Mazury in Olsztyn, 10-561 Olsztyn, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorota","family":"Uchman-Rze\u017cnik","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Collegium Medicum, The Mazovian University in P\u0142ock, 09-402 P\u0142ock, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6346-3200","authenticated-orcid":false,"given":"Gunawan","family":"Irianto","sequence":"additional","affiliation":[{"name":"Faculty of Health Science, University of Muhammadiyah Pringsewu, Lampung 35373, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7204-2871","authenticated-orcid":false,"given":"Dawid","family":"Pilewski","sequence":"additional","affiliation":[{"name":"Faculty of Health Science, Collegium Medicum, The Mazovian University in P\u0142ock, 09-402 P\u0142ock, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","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-Oncology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"iv1","DOI":"10.1093\/neuonc\/noaf194","article-title":"CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2018-2022","volume":"27","author":"Price","year":"2025","journal-title":"Neuro-Oncology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/s41572-024-00516-y","article-title":"Glioma","volume":"10","author":"Weller","year":"2024","journal-title":"Nat. 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