Moyamoya disease (MMD)-associated gene RNF213 has emerged as a critical player in the pathogenesis of a spectrum of cancers beyond its established role in MMD. This review synthesizes current understanding of RNF213’s structural characteristics, its fundamental functions, and its intricate associations with various malignancies. Mutations in RNF213 are strongly correlated with MMD risk, particularly in East Asian populations, and are linked to disease severity and age of onset. The gene’s role extends to the tumor microenvironment, where it influences cancer cell proliferation, migration, invasion, and immune evasion, as evidenced in gliomas, lung cancers, and breast cancers. Our analysis highlights the gene’s potential mechanisms in cancer development, including effects on mitotic abnormalities leading to genomic instability, modulation of cellular immunity, and metabolic reprogramming in tumor cells. We delve into the gene’s implication in immune responses and its potential as a biomarker and therapeutic target in oncology. Collectively, the evidence supports the notion of RNF213 as a tumor suppressor gene, whose mutations are associated with poor prognosis. The exploration of its role in cancer holds promise for advancing diagnostic and therapeutic strategies. Future research is warranted to elucidate the underlying mechanisms and to harness the full potential of RNF213 in cancer treatment.

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.

Panvascular diseases, characterized by systemic vascular dysfunction across multiple organ systems, represent a complex interplay of genetic susceptibility and environmental triggers. Ring Finger Protein 213 (RNF213), initially identified as the principal susceptibility gene for moyamoya disease (MMD), has emerged as a central regulator of panvascular pathophysiology. This review synthesizes current evidence elucidating RNF213′s multifaceted roles in vascular homeostasis, spanning its functions as an E3 ubiquitin ligase, mechanosensor, and immune modulator. The “second-hit” hypothesis posits that RNF213 mutations establish a genetic predisposition, while secondary insults—such as infection, hypoxia, or hemodynamic stress—precipitate pathological manifestations. Mechanistically, RNF213 orchestrates critical processes including endothelial integrity, angiogenesis, and inflammatory responses through pathways such as HIF-1α/VEGF, NF-κB, and Wnt signaling. Its dysfunction disrupts vascular remodeling, promotes aberrant smooth muscle proliferation, and exacerbates hypoxia-inflammation cycles, contributing to diverse pathologies ranging from intracranial aneurysms and arterial dissections to pulmonary hypertension and coronary artery disease. Emerging insights into RNF213′s interactions with gut microbiota, lipid metabolism, and epigenetic regulators further underscore its systemic influence. Despite advancements, unresolved questions persist regarding the context-dependent duality of RNF213 variants and organ-specific regulatory mechanisms. This review highlights the imperative for integrated approaches combining genetic, molecular, and environmental perspectives to unravel RNF213′s panvascular roles. We also outline unresolved questions regarding context-dependent effects of RNF213 variants and organ-specific regulatory mechanisms, and discuss potential avenues for future research integrating genetic, molecular, and environmental perspectives to advance understanding of RNF213′s panvascular roles.