Glioblastoma (GBM) is the most lethal and prevalent malignant brain tumor, with patients facing a median survival of 8 months and only 6.9% reaching five-year survival. The standard of care includes surgical resection of the tumor, radiotherapy, and concomitant chemotherapy with temozolomide. Despite aggressive multimodal therapy, GBM invariably recurs after surgical resection. However, the immediate impact of surgery on residual tumor biology remains poorly understood.

To investigate the impact of surgical resection on residual GBM tumor cell plasticity and TME, we developed sophisticated preclinical neurosurgical oncology models. We used two syngeneic GBM mouse models and one patient-derived xerograph and performed fluorescent-guided neurosurgery of sized-matched GBMs. For clinically relevant rodent models of neurosurgical oncology, we replicated each step of the neurosurgical procedure performed in patients with GBM and we used the same materials. In these models, we employed time-resolved bulk- and single-cell transcriptomics, proteomics, epigenomics, digital pathology, and intravital microscopy. Next, to examine the specific effects of surgical intervention on tumor progression in patients, we assembled an international, multicenter cohort of GBM patients who underwent two surgical procedures within a period of less than 10 days. For these particularly rare samples, we conducted a longitudinal investigation comprising neuropathological analysis, single nuclei and spatial transcriptome.

In both preclinical and clinical samples, we demonstrated that surgical intervention triggered a rapid cascade of events in the residual GBM. Specifically, surgery induces acute vascular disruption and leakage leading to profound hypoxia, which drives proneural-to-mesenchymal transition and extensive chromatin remodeling in tumor cells. This hypoxic environment fosters a robust immunosuppressive tumor microenvironment, characterized by increased infiltration of hypoxic tumor-associated macrophages, Tregs, and neutrophils, along with diminished antigen presentation. Comprehensive multi-omics inter- and intracellular network analyses demonstrated that postsurgical pathways converge on hypoxia-inducible factor (HIF)-1a as a central node. Critically, these post-surgical alterations confer increased resistance to conventional therapies.

These findings revealed a critical window of vulnerability immediately after surgical resection, suggesting that targeted interventions during this period could significantly improve GBM outcomes.