{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T14:48:07Z","timestamp":1793198887763,"version":"4.5.0"},"reference-count":142,"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\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p>Glioblastoma (GBM) remains a recalcitrant primary brain malignancy characterized by a profound immunosuppressive tumor microenvironment (TME), low mutational burden, and extreme molecular heterogeneity. Despite transformative successes in other solid tumors, clinical efficacy in GBM remains modest due to multifaceted barriers, including impaired antigen presentation, dominant myeloid suppression, and the restrictive blood\u2013brain barrier (BBB). This review provides a comprehensive synthesis of the immunotherapeutic landscape, encompassing checkpoint blockade, vaccines, oncolytic virotherapy, and adoptive cellular therapies. Diverging from traditional modality-centric descriptions, we propose an integrated framework organized around four core pillars of antitumor immunity: enhancing antigen presentation, reversing T cell dysfunction, reprogramming the suppressive TME, and engineering effective intracranial delivery. We detail mechanistic rationales and prioritize recent clinical breakthroughs, including bispecific T-cell engagers and the 2024\u20132025 milestones in bivalent and TEAM-CAR T cell designs. By delineating mechanisms of resistance and identifying areas of therapeutic convergence, we aim to outline research priorities to render the \u201ccold\u201d GBM niche permissive to durable antitumor immunity.<\/jats:p>","DOI":"10.3389\/fmed.2026.1848364","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T14:58:35Z","timestamp":1781708315000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Reconceptualizing glioblastoma immunotherapy: a four-pillar framework to overcome multidimensional resistance"],"prefix":"10.3389","volume":"13","author":[{"given":"Naibijiang","family":"Abuliezi","sequence":"first","affiliation":[{"name":"The Second Affiliated Hospital of Xinjiang Medical University","place":["Urumqi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiale","family":"Zhao","sequence":"additional","affiliation":[{"name":"The Second Affiliated Hospital of Xinjiang Medical University","place":["Urumqi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihan","family":"Sun","sequence":"additional","affiliation":[{"name":"The Second Affiliated Hospital of Xinjiang Medical University","place":["Urumqi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tayier","family":"Tuersong","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The Second Affiliated Hospital of Xinjiang Medical University, Urumqi","place":["Xinjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyi","family":"Dun","sequence":"additional","affiliation":[{"name":"The Fifth Affiliated Hospital of Xinjiang Medical University","place":["Urumqi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinfen","family":"Wu","sequence":"additional","affiliation":[{"name":"The Second Affiliated Hospital of Xinjiang Medical University","place":["Urumqi, China"]},{"name":"Xinjiang Key Laboratory of Neurological Disorder Research (Lab No.: XJDX1711)","place":["Urumqi, China"]},{"name":"Xinjiang Clinical Research Center for Neurological Diseases","place":["Urumqi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"574","DOI":"10.1001\/jama.2023.0023","article-title":"Glioblastoma and other primary brain malignancies in adults: a review","volume":"329","author":"Schaff","year":"2023","journal-title":"JAMA"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"700","DOI":"10.3390\/brainsci13121700","article-title":"Low-grade gliomas: histological subtypes, molecular mechanisms, and treatment strategies","volume":"13","author":"Toader","year":"2023","journal-title":"Brain 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