Approximately 90% of glioblastoma recurrences occur in the peritumoral brain zone (PBZ), while the spatial heterogeneity of the PBZ is not well studied. In this study, two PBZ tissues and one tumor tissue sample are obtained from each patient via preoperative imaging. We assess the microenvironment and the characteristics of infiltrating immune/tumor cells using various techniques. Our data indicate there are one or more regions with higher cerebral blood flow in PBZ, which we collectively name the “higher cerebral blood flow interface” (HBI). The HBI exhibited more neovascularization than the “lower cerebral blood flow interfaces” (LBI). The HBI tend to have increased infiltration of macrophages and T lymphocytes infiltration compared with that in LBI. There are more tumor cells in the HBI than in LBI, with substantial differences in the gene expression profiles of these tumor cells. HBI may be the key area of PBZ-targeting therapy after surgical resection.

Background: The IGFBP family of insulin-like growth factor binding proteins has important biological functions in the organism. However, the role of the IGFBP family in low-grade glioma (LGG) has not been fully explored.Methods: We validated the clinical value of the IGFBP family using RNA-seq and clinical data of LGG in the TCGA and constructed an IGFBPScore using LASSO-regression analysis for prognosis prediction, subtype determination, and treatment sensitivity determination. Subsequently, we explored the role of the IGFBP family in the development of LGG using PanCanAtlas data.Results: Our results suggest that most IGFBP family members were aberrantly expressed and were strongly associated with poor prognosis in LGG. By constructing an IGFBPScore representing the IGFBP family, we found that tumor samples with a high IGFBPScore had a glioblastoma-like mutation pattern characterized by IDH1wt, EGFRmut, PTENmut, and NF1mut with hypo-methylation and glioma stem cell (GSC) diversity. In contrast, the low IGFBPScore group was characterized by IDH1mut accompanied by TP53mut, CICmut, and ATRXmut, and had hyper-methylation status as well as the GSC restriction. Additionally, the high-IGFBPScore group had a high inflammation phenotype with increased immune antigenicity and increased infiltration of immune molecules and cells, as well as a high extracellular matrix phenotype and enhanced multiple metabolic pathways compared with the immune-quiet phenotype of the low-IGFBPScore group, which was strongly associated with poor prognosis.Conclusion: Our study provides a summary analysis and a theoretical basis for the biological role and clinical value of the IGFBP family in LGG, providing an important therapeutic target for LGG.

The presence of aneurysms, encompassing cerebral and abdominal aortic aneurysms, poses significant risks to individuals' health. The serum fatty acids (FAs) are implicated in various diseases, yet their causal association with different aneurysms remain less understood. In this study, the summary-level datasets associated with FAs and cerebral and abdominal aortic aneurysms from the UK Biobank and BioBank Japan were included. Two-sample Mendelian randomization (MR) analysis, replicated and reverse MR analysis were conducted to explore the causal association between serum FA levels with both cerebral aneurysm (CA) and abdominal aortic aneurysm (AA). The inverse variance weighting (IVW) was used as the primary method, together with sensitivity analyses for pleiotropy and heterogenous tests. As a result, the ratio of omega-6 FAs to omega-3 FAs serves as a detrimental effector of CA, and ratio of docosahexaenoic acid to total FA levels, omega-3 FA levels and ratio of omega-3 FAs to total FAs are beneficial effectors. Counterintuitively, monounsaturated FAs (MUFAs), ratio of MUFAs to total FAs, and omega-6 FAs serve as detrimental effectors of AA. Collectively, these results suggest novel serum FA levels of causal association with CA and AA, and shed light upon the distinct molecular underpinnings of the two types of aneurysms.

The nervous system is increasingly recognized as an active and integral component of the tumour microenvironment (TME), rather than a passive bystander affected by tumour invasion. Emerging evidence indicates that neural inputs shape tumour behaviour through both direct and indirect mechanisms. Neurotransmitters, neuropeptides and neurotrophic factors act on tumour cells, stromal cells, endothelial cells and immune cells to regulate proliferation, invasion, metastasis, angiogenesis, metabolic reprogramming and immune evasion. In parallel, the TME feeds back to the nervous system through inflammatory mediators, extracellular vesicles, axon guidance molecules and metabolic signals, thereby driving axonogenesis, tumour innervation, Schwann cell reprogramming, neuronal hyperexcitability and synaptic remodelling. These reciprocal interactions establish dynamic neuro–immune–metabolic feedback loops that sustain tumour progression and therapeutic resistance. Particularly in glioma and other highly innervated malignancies, activity-dependent neuron–tumour communication further highlights the functional integration between neural circuits and cancer. In this Review, we summarize the structural and molecular basis of neural components within the TME, discuss neurotransmitter receptor-mediated signalling and indirect regulation of immune, vascular, stromal and metabolic niches, and outline how tumour-derived signals remodel peripheral and central neural systems. We further highlight emerging therapeutic opportunities targeting β-adrenergic signalling, neurotrophin pathways, extracellular vesicle-mediated tumour innervation, Schwann cell-associated perineural invasion circuits, and neuron–tumour synaptic coupling. Finally, we discuss current translational challenges, including tumour-type heterogeneity, context-dependent neural effects, evidence-level heterogeneity and the need for spatially resolved biomarkers, and propose that incorporating the neural dimension into future mechanism-guided studies may inform biomarker-stratified trials and symptom-oriented interventions, with the long-term goal of improving both tumour control and neurological outcomes.

Brain metastases (BrM) develop within a highly specialized central nervous system niche shaped by the blood–brain barrier/blood–tumor barrier, brain-resident stromal cells, myeloid populations, and distinct metabolic constraints. Emerging studies suggest that bacteria-related signals can be detected in primary and metastatic brain tumors; however, their biological meaning remains incompletely defined. In particular, low-biomass brain tissues are highly vulnerable to reagent contamination, environmental carry-over, batch effects, and bioinformatic misclassification, making it essential to distinguish molecular bacterial traces from viable intratumoral bacteria or a bona fide tumor microbiome. In this review, we propose a graded conceptual framework that separates bacterial signals/elements, intratumoral bacteria, and intratumoral microbiota/microbiome according to evidentiary strength. We summarize current evidence for the spatial and cellular localization of bacteria-related signals in BrM and discuss potential source models, including primary-tumor carry-over, hematogenous dissemination, gut microbiota–derived metabolites, oral microbial input, and bacterial extracellular vesicles. We further examine how these signals may interact with the BrM tumor microenvironment by influencing tumor-cell stress adaptation, myeloid inflammatory niches, antigen-presentation pathways, vascular-barrier remodeling, and metabolic reprogramming. Particular attention is given to the emerging gut–brain–metastasis axis and to cancer-type-specific contexts in breast cancer, lung cancer, and melanoma brain metastases. From a translational perspective, bacteria-related signals in BrM may eventually contribute to biomarker development, patient stratification, and therapeutic modulation of the microbe–host axis. Nevertheless, current evidence remains insufficient to conclude that BrM broadly harbor stable, active, and clinically actionable microbial communities. Future progress will require multi-source matched cohorts, longitudinal sampling, stringent low-biomass contamination control, absolute quantification, spatial validation, functional models, and explicit separation of microbial presence, viability, and causality. A rigorous evidence-based approach will be essential for moving this field from intriguing associations toward biologically interpretable and clinically meaningful applications.

Observational studies have demonstrated associations between mental disorders and stroke, yet causal relationships and potential molecular mechanisms remain elusive. To clarify this, we performed a bidirectional 2-sample Mendelian randomization (MR) analysis using genome-wide association studies summary statistics to assess the causal effects of 7 major mental disorders (schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder, attention-deficit/hyperactivity disorder [ADHD], Alzheimer disease, and Parkinson disease) on stroke subtypes. Analyses were divided into discovery and validation cohorts of European ancestry, followed by MRlap and meta-analysis to obtain pooled estimates. To explore potential circulating protein mediators, 4907 plasma cis-protein quantitative trait loci (cis-pQTLs) from deCODE Genetics were screened, followed by Bayesian co-localization and 2-step MR mediation analyses. Our findings revealed that ADHD was consistently associated with an increased risk of any stroke (AS), any ischemic stroke (AIS), and particularly large-artery atherosclerotic stroke (LAS; odds ratio = 1.455; 95% confidence interval: 1.077–1.967). Mediators screening showed genetic liability to ADHD was linked to elevated circulating matrix metallopeptidase-12 (MMP12; β = 0.141, P = .005), which conferred protection against AIS and LAS, potentially lowering LAS risk by 7.5%. In conclusion, this MR study suggests ADHD is a causal risk factor for ischemic stroke, especially LAS. Paradoxically, circulating MMP12 acts as a protective mediator, modestly reducing this risk by 7.5%. These findings require validation in future experimental and cohort studies.