{
  "abstract": "Background: Glioblastoma (GBM) adapts to therapy through coordinated malignant-cell and microenvironmental responses, but the mechanisms linking treatment-associated inflammation to tumor-cell phenotypic plasticity remain poorly defined. Here, we investigated whether preoperative temozolomide exposure is associated with inflammatory-repair remodeling and a ROCK-linked therapeutic vulnerability in recurrent GBM using a window-of-opportunity clinical trial cohort. Methods: We integrated patient-resolved single-cell transcriptomics, spatial RNA profiling and multiplex protein imaging with experimental perturbations and orthotopic glioblastoma models. In the presurgical window-of-opportunity subgroup of NCT05236036, four patients with recurrent glioblastoma received additional preoperative temozolomide (TMZ; 150 mg/m2/day for 5 days) before resection and were compared with three recurrent comparators who did not receive additional preoperative TMZ. Results: Across seven tumors, malignant-cell inflammatory activity covaried with integrin-binding and wound-healing programs (median partial {rho} = 0.45 and 0.42, respectively). Tumors exposed to preoperative TMZ showed enrichment of inflammatory, chemokine, adhesion and wound-healing programs (GSEA q < 0.05), with the direction of enrichment preserved in all leave-one-patient-out analyses. In two tumors exposed to preoperative TMZ, CXCL12 localized to vascular territories, whereas chemokine and wound-repair programs increased near injury-reference regions. Across seven specimens analyzed by multiplex protein imaging, MYL9 abundance correlated with local CXCL12 ({rho} = 0.61), phosphorylated MYPT1 ({rho} = 0.48) and nuclear phosphorylated STAT3 ({rho} = 0.45), with positive associations in every specimen. Experimentally, TMZ increased CXCL8 and reactive-state markers and enhanced subsequent scratch closure, while CXCL8 and CXCL12 increased MLC2 phosphorylation. Fasudil attenuated TNF-NF-{kappa}B, inflammatory-response and IFN-{gamma}-response programs in TMZ-treated cells and reduced scratch closure and p-MLC2 in complementary assays. Across three orthotopic models, fasudil plus TMZ prolonged survival versus TMZ alone (model-stratified HR, 0.21; 95% CI, 0.07-0.61; P = 0.001). Conclusions: These findings link treatment-associated inflammatory-repair programs with cytoskeletal remodeling and support further translational evaluation of fasudil plus TMZ in glioblastoma.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA;Lou and Jean Malnati Brain Tumor Institute of th"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 27,
  "authors": [
    {
      "name": "R. Chojak"
    },
    {
      "name": "U. H. Faisal"
    },
    {
      "name": "P. U. Kumthekar"
    },
    {
      "name": "N. B. Drewes"
    },
    {
      "name": "L. Koutah"
    },
    {
      "name": "J. Jia"
    },
    {
      "name": "J. R. Turunen"
    },
    {
      "name": "M. C. O'Shea"
    },
    {
      "name": "V. Falkowski"
    },
    {
      "name": "A. Akhtar"
    },
    {
      "name": "S. Wang"
    },
    {
      "name": "J. Chen"
    },
    {
      "affs": [
        0
      ],
      "name": "S. Ahmed"
    },
    {
      "name": "H. Kazi"
    },
    {
      "name": "B. Auffinger"
    },
    {
      "name": "P. Jamshidi"
    },
    {
      "name": "K. McCortney"
    },
    {
      "name": "A. M. Catezone"
    },
    {
      "name": "M. C. Tate"
    },
    {
      "name": "R. Stupp"
    },
    {
      "name": "M. S. Lesniak"
    },
    {
      "name": "J. Miska"
    },
    {
      "name": "K. S. Dixit"
    },
    {
      "name": "D. Primdahl"
    },
    {
      "name": "D. H. Heiland"
    },
    {
      "name": "A. M. Sonabend"
    },
    {
      "affs": [
        0
      ],
      "name": "A. U. Ahmed"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/ed4c1g99kxyph.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.20.752931",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.20.752931v1.full",
  "id": "ed4c1g99kxyph",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.20.752931v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "cancer biology"
    ],
    [
      "openalex",
      "2716|Glioma Diagnosis and Treatment"
    ]
  ],
  "openalex": "W7213972657",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.20.752931v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-20",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/ed4c1g99kxyph.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:23:43Z",
      "native_id": "10.64898/2026.09.20.752931",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.20.752931v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:cancer biology",
      "subfield": "oncology"
    }
  ],
  "title": "Temozolomide-associated inflammatory-repair remodeling in recurrent glioblastoma exposes a ROCK-linked therapeutic vulnerability",
  "title_text": "Temozolomide-associated inflammatory-repair remodeling in recurrent glioblastoma exposes a ROCK-linked therapeutic vulnerability",
  "type": "preprint",
  "updated_at": "2026-10-30T12:23:43Z",
  "url": "https://research.draconitic.com/paper/ed4c1g99kxyph",
  "venue": "bioRxiv",
  "versions": []
}