Background:Glioblastoma is the most common and aggressive central nervous system malignancy with poor prognosis. Tumor-treating fields (TTFields), approved in China in May 2020, represents a significant advancement in GBM treatment. Leveraging the extensive real-world data accumulated in the Chinese Medical Information and Big Data Association (CHMIA) database, this study aims to assess clinical outcomes of Chinese patients with glioblastoma on TTFields therapy. Methods:This ambispective, observational study assessed post-marketing safety (data cut-off: November 15, 2021) and effectiveness (data cut-off: May 18, 2024) of TTFields in Chinese patients with newly diagnosed glioblastoma (ndGBM) and recurrent glioblastoma (rGBM). Safety outcomes included incidence and severity of skin adverse events (AEs); effectiveness was measured by overall survival (OS) and landmark OS rates. Results:Of 648 patients screened for this study, 315 were eligible and enrolled for analysis (ndGBM: n = 210; rGBM: n = 105). In the ndGBM cohort, the median OS was 19.9 months (95% CI: 13.4-24.8), with a 12-month OS rate of 63.5% (95% CI: 54.8-71.0). In the rGBM cohort, the median OS was 8.1 months (95% CI: 5.3-9.8), and 3-month and 6-month OS rates were 80.2% (95% CI: 70.4-87.1) and 58.7% (95% CI: 47.0-68.7), respectively. Most treatment-emergent AEs (TEAEs), including skin TEAEs, were mild to moderate (Grade 1-2). Conclusions:This study provided the largest real-world dataset to-date on TTFields in Chinese patients with glioblastoma. These patients showed survival outcomes similar to those in prior pivotal studies, without new safety concerns identified, supporting its use in Chinese glioblastoma population.

Glioma is a common malignant tumor of the central nervous system associated with poor prognosis, highlighting the urgent need for novel tumor suppressors. Here, we identify SERPINI1 (a serpini family member) as a tumor suppressor in glioma, with a focus on glioblastoma (GBM). Integrative analysis of TCGA, GEO, and CGGA datasets demonstrated downregulation of SERPINI1 in glioma versus normal brain tissues, with lower SERPINI1 expression associated with higher tumor grade and worse clinical outcomes. Functional assays showed that SERPINI1 suppresses glioma cell proliferation, migration, and invasion of GBM cells. Mechanistically, IP-mass spectrometry identified 167 SERPINI1-interacting proteins, including VRK1 and VRK3, which are involved in critical oncogenic pathways. Key interactions were validated by co-IP and Western blot, as well as by immunofluorescence co-localization assays. Furthermore, structural prediction demonstrated that SERPINI1 specifically targets the catalytic domain of VRK1/VRK3, potentially modulating their activity. Our findings establish SERPINI1 as a novel tumor suppressor in GBM and highlight its regulatory network as a potential therapeutic target.

Background Intracerebral hemorrhage (ICH) is frequently associated with poor clinical outcomes. White matter injury (WMI), particularly to the corticospinal tract (CST), plays a critical role in the development of hemiplegia. However, conventional ICH models tend to induce extensive damage and involve complex blood-derived components, highlighting the need for a model that can induce direct mechanical stress injury specific to white matter.Methods We established a novel mouse model by stereotactically injecting thermosensitive poly(N-isopropylacrylamide) (PNIPAM) hydrogel into the internal capsule to induce localized mechanical stress on CST. Resulting injury was evaluated by gross pathological examination and transmission electron microscopy. Motor function was assessed using a series of behavioral tests. CST integrity was examined by motor evoked potential (MEP) and nerve tract tracing. The underlying molecular mechanisms were elucidated by RNA sequencing (RNA-seq) and Western blot.Results The model consistently showed the induction of mechanical stress injury in internal capsule, leading to substantial WMI and motor deficits. MEP amplitude was reduced, and nerve tract tracing revealed severe disruption of the CST, which was more pronounced than that caused by the classical blood-injection ICH model. RNA-seq analysis identified the activation of mechanical stress-related pathways, including tumor necrosis factor (TNF) and fluid shear stress signaling pathways. Western blot assay confirmed the altered expression of WMI markers and upregulation of key molecules involved in these pathways.Conclusions This newly established model of mechanical stress injury effectively recapitulates the pathophysiology of CST damage following ICH. It also provides a simple and reproducible tool for conducting preclinical studies on mechanical stress-induced WMI in ICH.

Despite advancements in vascular reconstruction techniques, insufficient distal perfusion following ischemic stroke continues to cause irreversible neurological damage, and effective strategies for reconstructing functional microvascular networks remain inadequate. While vascular organoids have shown potential, their clinical translation is limited by the need for invasive surgical resection to accommodate large 3D grafts. This study improves the vascular organoid technology pipeline by developing hPSC-derived Pericyte-Enriched Vascular Assemblies. These assemblies are composed of CD31+ endothelial cells, PDGFRβ+ pericytes, and SMA-α+ smooth muscle cells, with pericytes accounting for 62.6% of the composition, making them the key cells determining the vascular organoid phenotype. After transplanting single-cell suspensions derived from these assemblies into the infarcted area, cerebral blood flow perfusion in mice was significantly restored, and sensory function improved. Mechanistic studies revealed that ischemic stress specifically upregulated the PRKCA signaling pathway in pericytes. Knockout of this kinase impaired the phenotype of the grafts, confirming its role as a master regulator of pericyte-mediated vascular remodeling. This study shifts the paradigm from structural biomimicry to function-driven design, highlighting the central regulatory role of pericytes in vascular organoid repair and providing new perspectives for cellular therapy and clinical treatment of ischemic stroke.

Both primary and metastatic brain malignancies are fatal and highly infiltrated with tumor-associated macrophages (TAMs). Enhancing the phagocytosis of neoplastic cells by TAMs is pivotal for slowing tumor growth. Great endeavors have been made to develop tyrosine kinase inhibitors (TKIs) for brain malignancies, yet whether tumor-targeting TKIs affect the phagocytic capacity of TAMs remains largely unknown. In this preclinical study, we report that repurposing ibrutinib, a blood-brain barrier-penetrable TKI, effectively suppresses the growth of several primary and metastatic brain tumors highly expressing Bruton's tyrosine kinase (BTK) or bone marrow X-linked nonreceptor tyrosine kinase (BMX) but concurrently dampens the TAM phagocytic function. Mechanistically, BTK, which is activated in TAMs, interacts with and phosphorylates Wiskott-Aldrich syndrome protein (WASp) to organize the actin cytoskeleton, which is imperative for phagocytosis. Ibrutinib treatment disrupts BTK-mediated WASp activation, thereby compromising TAM phagocytic efficacy. Pharmacological activation of WASp by its selective small-molecular activator EG-011 restores the ibrutinib-impaired TAM engulfment of tumor cells and effectively improves ibrutinib efficacy in mice bearing glioblastomas, primary central nervous system lymphomas, and lung carcinoma brain metastases. Furthermore, elevated expression of phosphorylated BTK or phosphorylated WASp in TAMs correlates with an increased phagocytic TAM subset identified by single-cell RNA sequencing and correlates with prolonged patient survival in a cohort with glioblastoma. Our preclinical study highlights the necessity of evaluating the on-target, off-tumor attack of TAMs during TKI administration and provides a proof of concept for reinvigorating the TAM phagocytic function to achieve additional clinical benefit.

OBJECTIVE:To introduce acellular dermal matrix (ADM) suturing as a novel repair method for intraoperative high-flow cerebrospinal fluid (CSF) leakage during transsphenoidal surgery (TSA), aiming to replace autologous fat/fascia lata grafts and reduce surgical morbidity. METHODS:Five patients (2 invasive pituitary adenomas, 2 craniopharyngiomas, 1 epidermoid cyst) underwent total sellar/suprasellar tumor resection and presented intraoperative high-flow CSF leakage. ADM grafts were tailored to dural defects and sutured directly to native dural edges. Outcomes included repair integrity, operative efficiency, and postoperative complications (CSF leakage, infection). RESULTS:All cases achieved dural closure without autologous tissue harvesting. Mean operative time was reduced by avoiding graft harvest procedures. No postoperative CSF leakage or intracranial infections occurred. At 30-day follow-up, all patients exhibited satisfactory recovery with stable skull base reconstruction. CONCLUSION:ADM suture repair eliminates donor-site morbidity and shortens operative time while providing robust dural sealing. This technique may be a promising alternative to conventional autologous grafts for high-flow CSF leakage management, warranting larger-scale validation.

Recurrence remains a critical challenge in patients with chronic subdural hematoma (CSDH) treated with middle meningeal artery embolization (MMAE), yet the underlying mechanisms and reliable predictors of this phenomenon remain poorly understood. Current predictors of recurrence rely on invasive or radiation-based techniques, prompting the need for non-invasive imaging markers. This study aimed to evaluate the 'rainbow sign aggravation' by arterial spin labeling (ASL) on the hematoma membrane as a predictor of CSDH recurrence after MMAE. We retrospectively studied ASL scans from 100 patients with CSDH who underwent MMAE between October 2022 and March 2025. The rainbow sign was defined as the hyperperfusion on the outer hematoma membrane. Inter-rater reliability, univariate analyses, and logistic regression were used to assess associations between the rainbow sign and recurrence. In the 100 patients who underwent MMAE, the pre-embolization rainbow sign was identified in 29 (29.0%) cases while the post-embolization rainbow sign was observed in eight (8.0%). Post-embolization rainbow sign and rainbow sign aggravation were significantly correlated with recurrence (P<0.001 for both), while no recurrence occurred in patients with a resolved rainbow sign. Subgroup analysis showed that rainbow sign aggravation was correlated with persistent headache (χ²=32.683, P<0.001), motor strength weakness (χ²=51.981, P<0.001), and worse neurological outcomes (χ²=33.076, P<0.001). The dynamic changes in the rainbow sign following MMAE correlated with the treatment response, with rainbow sign aggravation a significant predictor of hematoma recurrence. Integrating this marker into clinical assessments might enable personalized treatment strategies to reduce recurrence and improve outcomes in patients with CSDH.

Scar formation is a critical determinant of neurological recovery following spinal cord injury (SCI) because scars act as a physical support and barrier that influences axonal regeneration and remyelination. However, the regulatory mechanisms governing scar formation remain incompletely understood. Integrated multiomics analysis of publicly available single-cell RNA-seq and ATAC-seq data (GSE230765) from adult mice during the subacute/chronic phases of SCI revealed epigenetic mechanisms underlying microglial activation. Cell communication analysis revealed a connection between persistent microglial activation and excessive scar formation after SCI. Pharmacological inhibition of histone acetylation using L002 was employed to validate the H3K27ac-mediated regulation of the microglial phenotype, scar formation, and functional recovery. Persistent microglial activation post-SCI resulted in characteristic cholesterol metabolic reprogramming, with intracellular cholesterol accumulation correlated with sustained microglial activation. Single-cell ATAC-seq revealed chromatin accessibility-mediated epigenetic control of cholesterol metabolism gene expression, identifying H3K27ac as a pivotal regulator. L002-mediated H3K27ac inhibition attenuated cholesterol accumulation, mitigated neuroinflammation, and reduced scar formation through the disruption of microglia-astrocyte-fibroblast communication. Mechanistically, SPP1 secretion from activated microglia drove excessive scar formation, and inhibition of H3K27ac reduced the level of SPP1. Our study suggests that H3K27ac mediates the epigenetic regulation of myeloid cell activation in SCI pathogenesis. Targeted modulation of this histone modification site attenuates chronic microglial activation and subsequent scar formation, suggesting an innovative therapeutic strategy for neural repair. These findings establish chromatin remodeling as a promising target for improving functional recovery post-SCI.

Background:This study aimed to compare the nasal decolonization efficacy and comfort between chlorhexidine gluconate (CHG) and povidone-iodine (PVP) to provide an evidence basis for clinical guidance.Methods:A prospective, randomized, single-blinded, noninferior clinical trial was conducted in 174 patients with pituitary neuroendocrine tumors (PitNETs) who were scheduled to undergo transsphenoidal surgery. The noninferiority margin was delta=-0.1. The primary outcome was the effective rate of disinfection. The secondary outcomes included postoperative inflammatory indicators, the intracranial infection rate, and the proportion of intracranial infection.Results:The effective clearance rate of postoperative nasal bacteria was nonsignificantly different between the CHG and PVP groups (88.64% vs. 82.56%; between-group difference 6.10%; 95% CI [-5.30 to 17.50]). There was no significant difference in the incidence of postoperative central nervous system infections or serum inflammation-related indications between the two groups, but sterilization tended to occur quicker and last longer in the CHG group. CHG seemed to have advantages in terms of comfort, including less nasal irritation, less pungency, and better intranasal coloration.Conclusion:CHG and PVP have equal efficacy in nasal decolonization before transsphenoidal surgery, but CHG seems to have comfort-related advantages in terms of less nasal irritation, less pungency, and better intranasal coloration.

Hydrocephalus refers to the abnormal accumulation of cerebrospinal fluid (CSF) in the central nervous system, typically resulting from an imbalance between CSF production and absorption. Traditional classifications of hydrocephalus do not incorporate management strategies (not classified according to the degree of difficulty of treatment). Clinically, hydrocephalus that is challenging to treat is often categorized as refractory hydrocephalus (RH). However, the absence of a unified definition of RH impedes the standardization of treatment approaches, raising clinical dilemmas. This article explores the definition, etiologies, classification, and management strategies for RH. Based on the literature and the Diagnosis-Related Group payment system principles, RH is clinically defined as progressive hydrocephalus meeting one or more of the following criteria: (1) the absence of significant clinical or radiological improvement within 60 days despite standard interventions, usually due to pathological factors, such as abnormal CSF characteristics, (2) inability to achieve curative surgical treatments attributable to complex anatomy such as abnormal dynamic changes or multiloculated compartments, and (3) failure to respond after two consecutive therapeutic procedures. RH consists of six distinct subtypes, with infectious hydrocephalus being the most common, followed by low-pressure hydrocephalus. Temporary management strategies for RH must be carefully tailored to patient-specific characteristics, considering the risk–benefit analysis of available measures. In cases of infectious RH, achieving CSF sterilization and evaluating the results are crucial. Curative surgery for infectious RH should be performed only after CSF has been completely sterilized to normal levels. In low-pressure RH, a critical focus is identifying and addressing the sites receiving CSF.

Moyamoya disease (MMD) is a rare cerebrovascular disorder characterized by progressive steno-occlusion of the internal carotid artery system and aberrant collateral vessel formation. While MMD is primarily recognized for its arterial pathology, venous changes have been less explored. In this study, we investigated cerebral venous features in MMD and their association with disease progression. A total of 129 MMD patients (219 hemispheres) and 219 control patients with intracranial aneurysms (219 healthy hemispheres) were evaluated using digital subtraction angiography. MMD patients demonstrated significantly lower venous scores (cortical, deep, and total) compared to controls, with scores further declining as the disease advanced. Additionally, MMD patients exhibited delayed cortical venous filling times, which correlated with higher Suzuki stages. Venous drainage patterns also differed, with MMD patients predominantly showing posterior drainage, whereas controls exhibited anterior drainage. These findings underscore significant venous abnormalities in MMD, suggesting that the disease affects both the arterial and venous systems, challenging the conventional view of MMD as solely an arterial disorder.

Processes related to how the intracranial microvasculature initiates brain‒peripheral crosstalk for subsequent blood‒brain barrier (BBB) dysfunction at an early stage after subarachnoid hemorrhage (SAH) ictus are still unknown. This study elucidated the effect and potential mechanism of intracranial microvasculature-mediated T-cell infiltration on BBB function after SAH. Publicly available single-cell RNA sequencing data related to SAH ( https://ngdc.cncb.ac.cn/omix ; Accession No. OMIX006611) were retrieved and analyzed. The dataset was derived from the white matter region of adult male C57BL/6J mice at 1 and 7 days after experimental SAH. The SAH model was induced by endovascular perforation, and experiments were subsequently conducted at 1, 3, 7, and 14 days after SAH to evaluate T-cell infiltration, BBB integrity, neuronal injury, and neurological function. After SAH, CXCL12 expression was increased in endothelial cells and pericytes, promoting CD8+ T-cell infiltration via the CXCR4 pathway. This immune infiltration appeared to exacerbate BBB disruption and contribute to worsened neurological function. Blocking CXCL12-CXCR4 signaling with a CXCL12 neutralizing antibody or the CXCR4-specific inhibitor AMD3100 significantly reduced CD8+ T-cell infiltration, attenuated BBB damage and improved the neurobehavioral outcomes of SAH mice. This study suggests that, following SAH, both pericytes and endothelial cells may contribute to immune regulation by producing CXCL12, which promotes CD8⁺ T-cell infiltration into the brain. This mechanism may play a role in BBB disruption and neurological dysfunction. Targeting the CXCL12–CXCR4 axis could offer a potential approach for mitigating immune-mediated injury after SAH.

Blood–brain barrier preservation plays an important role in attenuating vasogenic brain edema after subarachnoid hemorrhage (SAH). This study was designed to investigate the protective effect and mechanism of artesunate, a traditional anti-malaria drug, on blood–brain barrier after SAH. Three hundred and seventy-seven (377) male Sprague–Dawley rats were subjected to endovascular perforation model for SAH. The rats received artesunate alone or in combination with Sphingosine-1-phosphate receptor-1 (S1P1) small interfering RNA (siRNA), antagonist VPC23019, or phosphatidylinositol 3-kinase inhibitor wortmannin after SAH. Modified Garcia score, SAH grades, brain water content, Evans blue leakage, transmission electron microscope, immunohistochemistry staining, Western blot, and cultured endothelial cells were used to investigate the optimum concentration and the therapeutic mechanism of artesunate. We found that artesunate (200 mg/kg) could do better in raising modified Garcia score, reducing brain water content and Evans blue leakage than other groups after SAH. Moreover, artesunate elevated S1P1 expression, enhanced phosphatidylinositol 3-kinase activation, lowered GSK-3β activation, stabilized β-catenin, and improved the expression of Claudin-3 and Claudin-5 after SAH in rats. These effects were eliminated by S1P1 siRNA, VPC23019, and wortmannin. This study revealed that artesunate could preserve blood–brain barrier integrity and improve neurological outcome after SAH, possibly through activating S1P1, enhancing phosphatidylinositol 3-kinase activation, stabilizing β-catenin via GSK-3β inhibition, and then effectively raising the expression of Claudin-3 and Claudin-5. Therefore, artesunate may be favorable for the blood–brain barrier (BBB) protection after SAH and become a potential candidate for the treatment of SAH patients.

Damage to endothelial cells (ECs) is a key factor in blood–brain barrier (BBB) disruption after intracerebral hemorrhage (ICH). While microtubules are essential for EC structure, their role in BBB injury remains unclear. Here we investigated the role of acetylated α-tubulin (α-Ac-Tub) in BBB integration after ICH. Using an autologous blood injection model in the striatum, we showed that the expression of α-Ac-Tub and MEC17, an α-tubulin acetyltransferase, significantly decreased along the vessels around the hematoma after ICH. Conditional MEC17 knockout in ECs further reduced α-Ac-Tub levels and exacerbated BBB leakage, brain edema, hematoma expansion, inflammation and motor dysfunction. Conversely, selective α-Ac-Tub upregulation in ECs via intravenous delivery of AAV-BI30-MEC17-GFP alleviated BBB dysfunction and improved motor recovery. Similarly, the HDAC6 inhibitor tubastatin A enhanced α-Ac-Tub levels, mitigating BBB damage and neurological deficits. Mechanistically, α-Ac-Tub deficiency in ECs reduced tight junction proteins (ZO-1 and Claudin5) and increased F-actin stress fibers through RhoA activation. Together, our findings highlighted α-Ac-Tub as a therapeutic target for restoring BBB function and reducing brain injury after ICH. Intracerebral hemorrhage (ICH) is a severe type of stroke with high mortality and disability rates. The blood–brain barrier (BBB), which protects the brain, often gets damaged during ICH, leading to further brain injury. This study explores how stabilizing microtubules can protect the BBB after ICH. The researchers used mice to study the effects of acetylated α-tubulin (α-Ac-Tub) on the BBB. They found that reducing α-Ac-Tub worsens BBB damage, whereas increasing it helps to protect the BBB. They used genetic techniques and a drug called tubastatin A to increase α-Ac-Tub levels in mice. This approach reduced brain damage and improved recovery after ICH. The study shows that α-Ac-Tub helps to maintain BBB integrity by preventing harmful changes in cell structure. These findings suggest that targeting α-Ac-Tub could be a new way to treat ICH and protect the brain. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

OBJECTIVE:This study utilized functional magnetic resonance imaging (fMRI) data to investigate cognitive function changes in trigeminal neuralgia (TN) patients and healthy controls (HCs), and to elucidate the potential mechanism. MATERIALS AND METHODS:The cognitive function of 34 patients with TN and 30 HCs was evaluated. Afterward, we calculated the amplitude of low-frequency fluctuations (ALFFs), regional homogeneity (ReHo), and degree centrality (DC). These metrics were correlated with cognitive performance using the Spearman correlation analysis. RESULTS:Patients with TN exhibited diminished cognitive performance compared to HCs. Increased mean ALFF (mALFF) levels were detected in the right temporal pole, superior temporal gyrus, and right insula in individuals with TN. These increases were negatively correlated with cognitive function. In contrast, decreased mALFF values were observed in the right lingual gyrus, bilateral calcarine, and left middle occipital gyrus, which were associated with improved cognitive function. Increased DC values were found in various areas, such as the right temporal pole, superior temporal gyrus, right opercular inferior frontal gyrus, bilateral medial superior frontal gyrus, left supplementary motor area, left anterior cingulum, and right middle cingulum in individuals with TN. These values negatively correlated with cognitive performance. CONCLUSION:TN patients exhibited impairments in multiple cognitive areas, such as attention, memory, executive function, visual perception and executive ability, information processing speed, and motor speed. The metrics ALFF and DC exhibited alterations in TN patients, suggesting that cognitive impairments may be linked to decreased functional activity in specific brain regions. Concurrently, certain cerebral regions may exhibit increased functional activity as a compensatory response to cognitive deficits. These findings hold significant theoretical value and clinical application potential, providing novel methodologies and perspectives for early diagnosis, personalized treatment, and efficacy evaluation. Such advancements are poised to enhance the overall treatment outcomes and quality of life for TN patients.

Traumatic brain injury (TBI) is a critical neurological disease with high mortality and long-term disability, which results in significant global health and socioeconomic burdens. The major diagnostic methods for TBI have some defects, such as being time-consuming, having poor specificity, and low sensitivity. Thus, it is highly essential to establish a rapid, high-sensitivity, and label-free detection method of TBI. Raman spectroscopy technique has been used in biochemistry due to its label-free and non-destructive. It is expected to detect and monitor the progression and regression of TBI from molecular perspective. In this paper, a novel strategy for TBI diagnosis through in vivo and ex vivo brain tissues based on Raman spectroscopy was proposed. The Raman characteristics of in vivo and ex vivo brain tissues in TBI mice models have been investigated for mild, moderate, and severe TBI degrees. It has been demonstrated that both the intensity and position of Raman characteristic peak of different degrees of TBI exhibited significant differences compared with the sham group. Crucially, some typical characteristic peaks associated with proteins, lipids, hemoglobin, and other biomolecules exhibited distinct trends correlating with trauma severity in the Raman spectra of in vivo and ex vivo brain tissues. It is suggested that Raman spectroscopy technique can be established as a rapid, label-free tool for in vivo TBI diagnosis, demonstrating high sensitivity for clinical prognosis assessment.

The diagnosis and treatment of gliomas depend greatly on the precise delineation of tumor boundaries and the rapid extraction of molecular pathological features. The development of high-resolution and high-sensitivity terahertz (THz) attenuated total reflection (ATR) imaging technology can greatly expand its application in the clinical medical field. In this study, we demonstrated a THz ATR imaging system based on a solid immersion lens (SIL). The resolution improvement mechanism by a solid immersion lens in the THz ATR imaging system has been studied theoretically and experimentally. According to the theoretical analysis results, the optimal parameters of the system have been selected. The spatial resolution of the THz imaging system was up to 120μm × 140μm. On this basis, the THz reflectivity of fresh normal brain tissue and glioma tissue in a mouse model was studied. Compared with the visible, MR, and H&E-stained images, the accurate identification of the glioma region boundary and microscopic structures in brain tissues was realized. The glioma regions in H&E-stained and THz ATR images were segmented automatically based on the Chan-Vese active contour model, where the performance evaluation rates were all above 95%. These promising results suggest that THz ATR imaging based on SIL could be used as a tool for label-free, high-sensitivity, and real-time imaging of brain gliomas.

Glioblastoma (GBM), the most aggressive primary brain tumor, is shaped by its integration into neural networks. While glutamatergic input is linked to tumor progression, the broader architecture and function of neuron-glioma connectomes remain unclear. Using monosynaptic rabies tracing, we map brain-wide neural input to patient-derived xenografts and reveal a consistent organizational logic: local inputs are primarily glutamatergic, while long-range connections exhibit diverse neurotransmitter profiles, with basal forebrain cholinergic projections emerging as a conserved input across sites. Functionally, presynaptic acetylcholine release promotes GBM progression through muscarinic receptor CHRM3 in a circuit-specific manner. Mechanistically, glutamatergic and cholinergic signals converge to enhance glioma calcium transients but diverge in temporal transcriptional control, with their dual blockade producing additive anti-tumor effects. Therapeutically, the anticholinergic drug scopolamine attenuates glioma growth, whereas the acetylcholinesterase inhibitor donepezil exacerbates disease. These findings reveal the complexity of neuron-glioma connectivity, highlighting long-range neuromodulatory pathways as promising therapeutic targets in GBM.