Gliomas, which originate from central nervous system (CNS) cells and account for 75% of malignant primary brain tumors in adults, are the most common type of primary brain tumor (1–5). Classically, tumor cell proliferation was regarded as an “autonomous” process driven by genetic defects, with neural signaling interactions considered secondary (6). However, recent evidence indicates glioma cells are active participants, expressing neuron-like ion channels and neurotransmitter receptors to decode neural signals and regulate invasion, metabolism, and drug resistance (7, 8).

In the normal brain, neurons form a complex signaling network through electrical activity and neurotransmitter release (e.g., glutamate, γ-aminobutyric acid (GABA)) to regulate cognition and movement, a process termed neural plasticity (9, 10). Histopathologic and lineage analyses confirm that neural stem cells (NSCs), glial progenitors (e.g., OPCs), and astrocytes are potential origins of gliomas (11–13). These cells are all involved in regulating nervous system plasticity in the brain (14). It is widely recognized that cancer arises from the dysregulation of homeostatic mechanisms governing tissue repair and stem cell self-renewal (15). In the adult brain, NSCs and glial progenitor cells exhibit characteristics associated with central nervous system cancers, including a strong proliferative potential and diversity (16). Meanwhile, NSCs are regulated by the same cellular pathways that are active in brain tumors, such as the Notch, Wnt, and NF-κB signaling pathways (17–19). In the stem cells of the adult brain, OPCs constitute a major proliferative population, uniformly distributed throughout the adult rodent brain (20, 21). Numerous studies have shown that OPC or earlier pre-OPC cells are present in various forms of gliomas (22, 23). Dysregulation of myelin plasticity promotes glioma cell proliferation in primary brain cancer (24). Synaptosomal-associated protein 25 (SNAP25), a synaptic plasticity protein, is significantly correlated with the progression of glioma (25, 26). In summary, neuroplasticity is closely linked to the initiation and progression of gliomas, particularly in myelin plasticity. Aberrant plastic repair mechanisms may drive the development of gliomas, while post-glioma repair processes can further promote glioma progression.

This review summarizes current knowledge on glioma-neuron interactions from the perspective of neuroplasticity, dissecting the intricate mechanisms and structural alterations underlying neuroplasticity. Previous studies have discussed the interrelationship between myelin plasticity and glioma-neuron interactions, proposing that gliomas hijack myelin growth signals to promote self-proliferation (27, 28). Based on these findings, we analyze the relationship between normal neuroplasticity and abnormal glioma behavior in terms of proliferation, migration, stem-like properties, and immune interactions. We further explore the impacts of local neural signals, remote neural signals, and external signals on gliomas ( Figure 1 ). We found that glioma-neuron interactions closely resemble the mechanisms of neuroplasticity, but disrupt the homeostatic balance inherent to normal neuroplasticity. The objective of this review is to delineate the correlations between neuroplasticity and glioma-neuron interactions, offering promising future directions for research.

Neuroplasticity refers to the brain’s capacity to reorganize its structure, function, or connectivity in response to intrinsic or extrinsic stimuli, a process that elicits both functional and morphological alterations. This dynamic process allows us to adapt to different environments and plays an important role in learning, memory, and injury recovery (29). It is well known that neurons in the adult brain are not regenerative upon death (30). Consequently, the remodeling following injury and learning primarily relies on the regrowth and reinnervation of axons (31). Axonal growth forms or strengthens more synaptic connections. Synaptic connections are highly plastic, with the number and strength of synapses changing significantly during development or in response to training (32).

Glia cells act as active regulators of neuroplasticity through their interactions with neurons and exhibit structural plasticity during learning (33, 34). The glia-neuronal crosstalk differs in physiological conditions and various brain disorders (35). Axonal growth relies on the regeneration of myelin sheaths. During the development of the brain, Oligodendrocytes (OLs) are the myelinating cells of the CNS that are generated from OPCs (36), which proliferate and differentiate during embryonic development. OPCs originate in the subventricular zone (SVZ) (37). However, to promote brain repair, OPCs are typically distributed throughout the gray and white matter, where they exhibit strong proliferative and migratory capabilities, as well as the constant capacity for surveillance (20, 38). During the development, myelin sheaths are “optimally distributed” throughout the nervous system. After developmental maturation, OPCs generate OLs involved in adaptive myelination (39). Neuronal activity, learning, and socialization influence myelin formation, this dynamic change in turn regulates signaling in neural circuits and is associated with emotional and cognitive functions, known as “myelin adaptation” (40) ( Figure 2 ). Consequently, neuroplasticity can be summarized as three interrelated aspects of axonal plasticity myelin plasticity, and synaptic plasticity, which together form the basis of brain adaptation and plasticity.

Studies have shown that neuronal activity can drive glioma progression via synaptic connections (7, 8), with early neuronal activity found to promote OPC proliferation and differentiation (41). A mouse model in which general anesthesia was used to reduce neuronal activity has demonstrated that low neural signals inhibited the growth and invasion of patient-derived glioblastoma (7). In normal physiological conditions, neural signals from external sensory stimuli can directly impact glioma development, and manipulating olfactory receptor neuron activity influences glioma progression (42). Additionally, stimulation of optic nerve activity promotes optic nerve glioma growth, while reducing visual input inhibits tumor formation and maintenance (43). Surprisingly, radiotherapy—a common treatment modality—accelerates tumor growth by enhancing neuronal activity (44). Collectively, these results indicate that neural signals promote glioma proliferation and differentiation, with such signals being moderately associated with learning and remodeling of the nervous system.

It is well established that the dissemination of glioma cells contributes to their incurability (88), yet this process differs fundamentally from the metastasis of other solid cancers, which typically do not spread to distant organs (89). There are several possible reasons: First, although glioma cells bind to blood vessels, they may not be able to break through the basement membrane into the vasculature system (90). Second, extra-neural tissues may lack an appropriate growth microenvironment to support glioma proliferation. Clinical investigations have shown that following complete resection, postoperative recurrence predominantly occurs in the local white matter (91). The neuronal soma resides in the gray matter, while axons—including those forming the corpus callosum, the largest interhemispheric commissure—occupy the white matter, which is composed of a broad array of neural fibers (92, 93). Gliomas that spread along the white matter bundles of the corpus callosum are called butterfly gliomas (94). The prognosis for these patients is often poor, and severing the corpus callosum can largely prevent the spread of gliomas (83). The axonal architecture in the white matter creates a more permissive microenvironment for the dissemination of glioma cells.

White matter, situated beneath the gray matter cortex, consists of myelinated neuronal fibers that facilitate rapid signal transmission within the brain (95). Myelin plays a critical role in tumor spread. It serves as a highly permissive substrate for glioma cell adhesion and migration (96). The microenvironment of the CNS inherently exhibits resistance to glioma cell infiltration. Inhibitory molecules in CNS myelin (e.g., Nogo/Semaphorins/Ephrins, etc.) also suppress glioma cell migration and proliferation (97). This is based on another crucial function of myelin: to prevent excessive axonal regeneration, sprouting, and cellular infiltration into the brain parenchyma (98). Neuronal activity induces adaptive changes in myelin structure and function. Correspondingly, this activity significantly influences the invasive behavior of glioblastoma cells, including the formation, growth, and movement of TMs (99). Neurons paradoxically exhibit tumor-promoting effects on gliomas, though emerging studies reveal that adult post-mitotic neurons can induce apoptosis in both murine and human glioma cells (100). Moreover, in vitro co-culture reveals that the migratory ability of glioblastoma cells is inhibited by contact with neurons (101). The underlying mechanism may involve neuron-regulated glioma cells exhibiting characteristics resembling those of OPCs (8). Overall, neurons normally regulate OPCs to promote myelination repair, but may pathologically facilitate glioma migration along axons by misidentifying tumor cells as OPCs.

The cellular composition of glioma is not homogeneous (102). Glioma cells with stemness, called glioma stem cells (GSCs), promote heterogeneity and drug resistance in gliomas (103). As normal stem and progenitor cells participate in tissue development and repair, these developmental programs re-emerge in CSCs to support the development and progressive growth of glioma (104). Current research suggests that GSC may be derived from NSCs residing in the SVZ in adults, as they share many common features (105, 106). The researchers believe that if GSCs are the glioma cells responsible for generating the tumors, then the developmentally analogous relationship is the NSC-OPC axis (107). In fully developed individuals, NSCs can differentiate into OPCs as the primary source of myelination contribution (108). Olig2 is highly expressed in OPCs as well as in GSCs (109). Culturing glioma cells with conditioned medium from OPCs, which contains secreted factors, indicates that soluble factors secreted by OPCs enhance the stem-like properties of glioma cells, thereby contributing to tumorigenesis, therapeutic resistance, and recurrence (110). OPCs and macrophages/microglia form a distinct microenvironment for glioma cells at the tumor boundary, with particularly prominent aggregation in recurrent lesions. In this microenvironment, OPCs may drive the acquisition of stemness in glioma cells (91, 110, 111). Neuronal activity enhances the stemness of glioma cells. Studies have shown that exosomes derived from active neurons promote glioma progression and radioresistance by inducing phenotypic and metabolic transformation of GSCs (112). In summary, we suggest that the aggregation of OPCs at the tumor may misregulate the enhancement of glioma stemness, and this regulation can be potentiated by electrical activity stimulation.

In addition to directly mediating tumor growth, neurons can promote the tumor by modulating immune cell function. Astrocytes perform supporting functions for neurons and oligodendrocytes (113). Microglia are recognized as mononuclear phagocytic cells that play a significant role in immune response and homeostasis within the CNS (114). They contribute to the formation, maintenance, and reshaping of neuronal circuits by clearing dead cells and participating in neural repair through pruning (115, 116). In neuroplasticity, complex interactions between neurons, T cells, and microglia (117). Neurons play a crucial role in regulating microglia activation, as neurons secrete factors such as CD200 (118), SEMA3A (119), and CX3CL1 (120) can modulate microglial cell properties to different degrees. Whereas this regulation promotes the process of neuronal repair and remodeling in the normal brain, in the glioma setting, neurons produce reduced mid-term to activate T cells, which in turn leads to an increase in T cell Ccl4 secretion and microglial cell secretion of Ccl5 to sustain glioma cell growth (117).

Overall, while glioma growth stimulates immune cell repair and participates in neural remodeling, signaling impulses from neurons can, in turn, facilitate this process. However, this process seems to be exploited by the glioma cells for the use of self-growth.

Neuron–glioma interactions are bidirectional. Based on subdural electrocorticography, sampling of normal and glioma-infiltrated cortex during speech showed that glioma infiltration affected the brain’s ability to encode information during nuanced tasks (121). Recent studies have revealed that tumor-associated cortical networks exhibit hyperexcitability (8). Tumor-induced disruption of synaptic network activity in the peritumoral region leads to alterations in network excitability (122). Although neuronal over-excitation maintains task-specific neuronal responses, the tumor-affected cerebral cortex loses the ability to decode complex words (123).

In addition to impairing brain function, epilepsy is diagnosed in 70–90% of patients with glioma (124). However, further investigation has revealed that the abnormal enhancement of peritumoral neuronal network activity and the prevalent epileptiform activity were closely associated with the formation of new synapses, with glioma cells forming these new synapses remaining as OPC-like cells (125). In the glioma-surrounding tissue, extracellular glutamate levels were found to be 100 times higher than in the unaffected brain (126). Glutamate secretion from gliomas stimulates peritumoral neuronal receptors, leading to neuronal hyperexcitability and epileptic seizures (127).

There is growing evidence that different types of cancers originate from distinct “progenitor cells”, which undergo the first or multiple genetic hits leading to the onset of cancer (128). Therefore, the origin and progression of cancer cells in different locations depend on the surrounding environment and cell type. Gliomas, the most prevalent primary malignant tumors in the adult CNS, are likely triggered by the daily remodeling and repair processes of glial cells, during which multiple factors induce malignant changes. OPCs, the most active stem cells in the brain and responsible for myelin plasticity, are also found aggregating around gliomas.

The underlying mechanism of this OPC aggregation—whether driven by reparative recruitment or malignant transformation during the initial repair process—remains inconclusive. Mosaic Analysis with Double Markers (MADM)-based lineage tracing revealed significant abnormal growth prior to malignancy only in OPCs (129). Notably, accumulating evidence has established that OPC aggregation significantly accelerates glioma progression. Stem cells not only have the mission of proliferation and differentiation but also require multiple factors (e.g., neuroregulatory signals, paracrine factors) to promote or inhibit the function (130). Similarly, in gliomas, the factors that regulate OPC also regulate the glioma cells and even form similar synaptic connections. It seems that brain cancer learns the mechanisms of neural plasticity.

However, these regulators also exhibit bidirectionality. As a key modulator of synaptic plasticity (72), BDNF contributes to physiological synaptic regulation through neuronal activity and drives tumor progression through BDNF-TrkB-mediated malignant synapse enhancement (28). Its effects are not unilaterally protumorigenic: mature BDNF/TrkB signaling drives glioma growth, migration, and anti-apoptotic effects, while proBDNF/p75NTR activation inhibits these processes (131). Additionally, lncRNA BDNF-AS suppresses malignancy by targeting RAX2 (132). This functional difference depends on the type of cells involved, the selective binding of receptor subtypes, and microenvironmental characteristics (66). GABA shows more pronounced bidirectionality (133). In DMG, NKCC1-mediated high intracellular Cl^- converts the action of GABA to membrane depolarization, promoting proliferation (51). Additionally, GABA maintains GSC quiescence for post-surgical recurrence (134). Conversely, GABA_aR activation inhibits proliferation in low-grade gliomas via enhanced inhibitory signaling, although a mechanism potentially weakened by GABA_aR downregulation in glioblastoma (135). In vitro experiment, neuronal GABA_aR activation directly suppresses glioma growth (136). This bidirectionality resembles the functional differences of GABAergic signaling in OPC regulation (47). This suggests that targeted modulation of Cl^- currents in glioma cells may provide a novel therapeutic approach to halt tumor progression (137).

Current experimental models of tumor-neuron interactions predominantly rely on in vitro cell co-culture (138) or xenografts in immunodeficient mice (8, 61). Though they partially reflect the interactions between gliomas and neurons, they cannot replicate the 3D structure of in vivo neural circuits, neurotransmitter microenvironment, or brain region-specific neuroplasticity. However, related studies have made progress. An in vitro 3D model constructed using 3D bioprinting technology, consisting of an outer hemisphere containing neurons and an inner hemisphere containing glioma cells (139). Modeling glioblastoma invasion using human brain organoids (140). Co-culture system using patient-derived GBM organoids and human induced pluripotent stem cells (hiPSCs) (141). Despite these advancements, further optimization is still needed to more realistically simulate the physiological environment of tumor-neuron interactions in vivo. Another important consideration is that there are significant differences between pediatric and adult gliomas in terms of genetic background, site of origin, and clinical behavior (142). Adult gliomas often originate in the supratentorial region and are often accompanied by neuroplastic compensatory mechanisms. In contrast, pediatric gliomas predominantly occur in brain regions with active neurogenesis, including the brainstem and thalamus. The progression may be more closely linked to the active neuroplasticity during the brain development stage (143). Therefore, it is necessary to study the differences between the contributions of “developmental neuroplasticity” and “pathological neuroplasticity” in childhood and adult gliomas.

Molecules related to neuroplasticity may serve as potential targets for glioma treatment, but the specific mechanisms remain unclear. ADAM10 is highly expressed in gliomas; however, the mechanism by which ADAM10 balances neuroplasticity and glioma phenotypes through cleaving different substrates remains elusive (64). AMPAR is the core subtype of glutamate receptors. Pharmacological inhibition of AMPAR activity using Talampanel has demonstrated potential in the clinical management of newly diagnosed glioblastoma (144), but the impact of long-term AMPAR inhibition on normal neurological function has not yet been systematically validated. Cav3, as a T-type calcium channel in synaptic plasticity, can be utilized in inhibiting glioma development through disconnecting nerve cell and OPC-like glioma cell interaction (145, 146). Rabies-mediated genetic ablation of neurons halts glioblastoma progression (44). Unexpectedly, some commonly used drugs have been found to have tumor-promoting effects, such as Lorazepam (51). Currently, there is growing evidence that multiple neuroplasticity signals are exploited to influence the progression of gliomas, suggesting that learning and remodeling are closely related to the initiation and progression of gliomas. We believe that broader plasticity regulatory mechanisms can inspire the study of abnormal tumor proliferation. Meanwhile, based on the study and modulation of neuroplasticity, more effective treatments for controlling the progression of gliomas will be discovered.