Early studies suggested this integration by showing that glioma cells and cell lines express a diverse range of functional neurotransmitter receptors, including glutamate, GABA, acetylcholine, and others [18,19,20]. Cultured human glioma cells were demonstrated to respond to these neuroligands with intracellular calcium signals, indicating that they were able to “listen” to neural transmission [21]. It is now clear that this communication is not purely paracrine, but takes place via specialized, synapse-like junctions.

Researchers used high-resolution electron microscopy to reveal direct, bona fide synapses between presynaptic neuronal axons and postsynaptic glioma cell membranes [14,22] (Fig. 1). These neuron-glioma synapses have the characteristics of canonical interneuronal synapses, such as vesicle-filled axonal boutons and postsynaptic densities, which provide a physical substrate for direct, fast, and activity-dependent signal transmission [14]. The protein makeup of these interfaces is also being researched, with synaptic proteins such as bassoon, DLG4, and HOMER1 being studied in glioma [23].

To trace the origins of these inputs, researchers used sophisticated techniques such as retrograde monosynaptic rabies virus tracking [24]. Yang et al. used this approach to generate a brain-wide connectome map for xenografted human GB, revealing a consistent organizational logic: tumors receive dense local inputs, primarily glutamatergic, as well as diverse, long-range inputs from various subcortical neuromodulatory systems, including cholinergic neurons from the basal forebrain [2]. Other investigations employing similar approaches have verified this extensive neuroanatomical integration, exhibiting different electrical features of the glioma-innervating neurons [25,26,27,28]. This integration is a critical component of glioma biology, allowing the hijacking of the brain’s signaling apparatus. To support this integration notion, certain investigations have shown that glioblastoma cells can be reprogrammed or forced to develop into neurons or oligodendrocytic cells, blurring the distinction between neoplastic and neural cell identities [29,30,31]. Communication at this contact is also mediated by gap junctions, with connexins 30, 36, and 43 involved in both normal brain function and brain malignancies [32].

The structural integration of gliomas is accompanied by significant functional effects. Neuronal activity is no longer viewed as simply background noise, but rather as a powerful driver of tumor growth [13]. Optogenetic activation of cortical neurons surrounding a glioma xenograft was found to greatly boost tumor cell proliferation, indicating a clear causal relationship between brain activity and glioma growth [13]. This effect is mediated, in part, by the activity-dependent production of molecules that promote tumor growth, such as neuroligin-3 (NLGN3) and brain-derived neurotrophic factor (BDNF) [13,33]. Furthermore, neuronal activity from remote brain regions can promote glioma growth by releasing signaling proteins such as semaphorin 4F (SEMA4F) [34].

At the synaptic level, this functional integration manifests as neurotransmitter-driven electrical activity in glioma cells. Action potentials in presynaptic neurons cause the release of glutamate, which activates AMPA receptors on glioma cells, resulting in depolarization and calcium influx, which promotes proliferation and invasion [14]. This generates a vicious feedback loop, as gliomas can cause neuronal hyperexcitability and seizures by releasing excess glutamate, which then drives tumor growth [14,35]. Indeed, the relationship between neurotransmitters and glioma-associated seizures is the subject of much clinical and scientific study [16,35,36]. This malignant feedback loop emphasizes gliomas’ profound and damaging integration into the brain’s functioning networks. In regard to tumor-promotive signals, while the synaptic release of glutamate and neuromodulators from active neuronal networks is the most important contributing factor, glioma cells are additionally capable of modifying the landscape of neurotransmitters. In fact, the export of glutamate via the system X_c⁻ is an exemplary pathway, as it participates simultaneously in redox balance by importing cystine. An additional pathway, which is emerging as important but for which results so far are limited to the literature on glioblastomas and monoamine neurotransmission, is the possible utilization of the molecular components of the monoamine system by glioblastoma cells (Fig. 2).

As the main excitatory neurotransmitter in the central nervous system (CNS), glutamate is possibly the most researched neurotransmitter in the setting of glioma, where it plays a central and diverse pro-tumorigenic role [35,37,38].

GABA, the brain’s primary inhibitory neurotransmitter, plays a more nuanced and context-dependent role in glioma development than glutamate [62]. While some studies have suggested that GABA has a tumor-suppressive role by blocking cytokine production from glioma cells [63], others have found that altering GABA signaling can influence the formation of glioblastoma spheroids [64]. The expression of GABA-A receptor subunits is associated with tumor histology and clinical prognosis, demonstrating their clinical importance [65]. However, the most striking finding has been GABA’s paradoxical excitatory and pro-tumorigenic involvement in some glioma subtypes. In diffuse midline gliomas (DMGs), GABAergic synaptic transmission increases tumor development [66]. This is owing to an altered chloride gradient in tumor cells, resulting in GABA-A receptor activation that is depolarizing rather than hyperpolarizing [66]. The expression of chloride transporters such as SLC12A5 (KCC2) is thus an important predictor of the GABAergic response in glioblastoma [67]. Furthermore, glioma cells can have altered GABA metabolism, with the generation of gamma-hydroxybutyrate (GHB) being a key factor in maintaining a proliferative, stem-like state [68]. These findings indicate extraordinary adaptability in how gliomas can exploit even inhibitory signals to their benefit.

The cholinergic system, a fundamental regulator of cortical arousal and plasticity, has recently been identified as a critical long-term modulator of glioma growth [2,69]. Yang et al. describe how cholinergic neurons in the basal forebrain create functional synapses with GB cells, and the release of acetylcholine (ACh) at these junctions stimulates tumor proliferation and invasion [2]. This impact is predominantly mediated by the metabotropic muscarinic M3 receptor (CHRM3) [2]. Other investigations have confirmed the pro-tumorigenic effect of muscarinic signaling in GSCs, revealing that blocking these receptors prevents tumor growth [70,71]. Beyond muscarinic receptors, nicotinic ACh receptors are expressed on glioma cells and can be regulated by a variety of drugs, with certain neurotoxic inhibitors promoting growth [72]. The clinical relevance is highlighted by the discovery that systemically administered drugs can have an effect; for example, neuromuscular blocking agents such as atracurium can promote astroglial differentiation and deplete the GSC pool [73], whereas the anesthetic midazolam can epigenetically influence cholinesterase gene expression [74]. It has also been revealed that human glioblastoma cells can differentiate into cholinergic neuron phenotypes, demonstrating the tumor cells’ flexibility [28]. The identification of the ACh-CHRM3 axis as a driver of GB growth has important therapeutic implications, indicating the possibility of repurposing anticholinergic drugs [2].

Dopamine signaling has a role in a variety of neurological activities, and dysregulation is key to disorders such as Parkinson’s and schizophrenia. In glioblastoma, the dopamine system, namely the D2 receptor (DRD2), has emerged as a difficult but potential therapeutic target [75,76].

DRD2 is overexpressed in GB, particularly in GSCs, and activation has been demonstrated to accelerate tumor growth [77,78]. A genome-wide screen identified DRD2 as a major mitogenic signaling hub that interacts with the epidermal growth factor receptor (EGFR) pathway [79,80]. DRD2 activation causes substantial transcriptome and metabolic plasticity in GB cells, which contributes to aggressive behavior and treatment resistance [81,82]. Chronic stress, a known modulator of dopamine signaling, can hasten GB growth via a DRD2-dependent axis [83]. Glioma formation can also affect striatal dopaminergic function in the host brain [84].

This pro-tumorigenic activity makes DRD2 an appealing target. Many antipsychotics are DRD2 antagonists that can pass the blood-brain barrier. Preclinical investigations have demonstrated that medicines such as thioridazine, haloperidol, and pimozide can decrease glioma growth [80,85]. This has sparked a great interest in repurposing these psychiatric medications for GB treatment [85]. Dopamine signaling appears to alter glioma cells’ physical features, which contribute to their spheroid forming behavior [86]. The effect of dopaminergic action on the glioblastoma niche is a current research topic [87].

Other monoamines contribute to the complex biology of GB [75]. Serotonin (5-HT) has been studied for its possible application in targeted imaging, as glioma cells produce serotonin transporters [88]. Serotonin can also influence the expression of immune genes such as MHC class II on glioma cells, implying a role in neuro-immune interactions at the TME [89]. The involvement of the serotonergic system in other brain diseases raises concerns regarding its function in the neurological and behavioral symptoms associated with glioma [90]. More recent work has continued to support the relevance of the serotonergic axis in GB by demonstrating expression and distribution of key serotoninergic system proteins in glioblastoma samples and datasets, with subtype-specific patterns reported across tumors. This supports the concept that serotonin-related machinery may contribute to intratumoral heterogeneity and could help explain patient-to-patient variability in neuromodulator responsiveness. From a translational perspective, the presence of serotonin transport and receptor components strengthens the rationale for serotonin-pathway imaging strategies and invites further investigation into whether serotonergic signaling participates in immune remodeling or adaptive resistance programs [91].

NE appears to play a contrasting, perhaps tumor-suppressive role. One study discovered that NE suppresses the migration and invasion of glioblastoma cells in vitro, perhaps by inhibiting MMP-11 [92]. However, the larger catecholamine system, which includes both dopamine and norepinephrine, has been linked to glioblastoma formation, indicating a complicated interaction [93,94].

Monoamine oxidases (MAOs) regulate monoamine metabolism. Monoamine oxidase A (MAO-A) is overexpressed in gliomas, and inhibiting it has been demonstrated to slow glioma growth, making it a prospective therapeutic target [95,96]. Glucocorticoids and androgens can promote MAO-A expression, which connects stress and hormonal signaling to glioma biology [97].

Chemical communication within the glioma TME expands beyond the traditional neurotransmitters to include a variety of additional signaling chemicals.

The most urgent therapeutic option is to repurpose medications that have already been licensed for neurological or psychiatric conditions [85].

From the near-term clinical viewpoint, those most actionable pathways are represented by glutamate/AMPA/system X_c⁻ signaling given seizure overlap and existing anti-glutamatergic drugs; CHRM3-driven cholinergic inputs; and DRD2 signaling leveraging BBB-permeable antagonists, besides MAO-A inhibition. Each is supported by repurposable neuroactive compounds and emerging translational evidence (Fig. 3).

Beyond repurposing, a better knowledge of the neuro-glioma relationship will drive the creation of new treatments. These could include highly specific receptor antagonists, tiny compounds that disrupt neuron-glioma connections, or even gene treatments that suppress critical receptor genes via RNA interference [118]. Another interesting approach is to use aptamers as molecular recognition elements for CNS diagnostics and therapies [119]. Advanced drug delivery strategies, such as convection-enhanced delivery, may be required to cross the BBB and effectively deliver these medicines to the tumor location [6].

Transforming these intriguing ideas into clinical success necessitates overcoming considerable challenges. The BBB remains a significant challenge for several potential medicines [120]. GB’s considerable inter- and intratumoral variability makes a “one-size-fits-all” strategy difficult to succeed [121,122]. A future technique could include assessing a patient’s tumor for a unique neurotransmitter receptor expression signature to guide tailored therapy. Finally, the potential risk of on-target neurological side effects from systemically altering neurotransmitter systems is a major worry that must be addressed through targeted delivery, careful dosing, or the discovery of therapies with greater tumor selectivity.

Key limitations include the predominance of preclinical models, incomplete mapping of receptor expression across the GB subtypes, and difficulty in distinguishing neuronal versus tumor-derived neurotransmitter effects within patient tissues. Moreover, BBB penetration and on-target CNS toxicity remain central constraints that underscore the need for biomarker-guided stratification and targeted delivery strategies.

The future of glioma therapy will most likely involve multi-pronged strategies that combine traditional cytotoxic treatments with techniques that alter the tumor’s permissive microenvironment. This could include combination therapy that target both glutamatergic and cholinergic signaling [2], as well as combining a DRD2 antagonist with EGFR inhibitors. The ultimate goal is to change the brain’s permissive, supporting environment into one that is hostile to tumor formation.