This review explores the intrinsic and microenvironmental factors driving glioblastoma (GBM) invasion. GBM is a highly aggressive brain tumor with poor prognosis due to its invasive nature and recurrence. Recent single-cell studies have revealed molecular mechanisms enabling glioma cells to invade normal brain tissue. The review discusses intrinsic biological drivers of tumor cell invasion, including interactions between tumor cells and the tumor microenvironment (TME). It highlights the role of the neuronal niche in the TME, which contributes to glioma growth and invasion. The mechanisms of invasion promoted by astrocytes and immune cells are also addressed. The review also covers current literature on therapeutic targeting of invasion mechanisms. GBM cells exhibit varying invasive and proliferative capacities, with different cell states contributing to tumor progression. Tumor microtubes (TMs) and tunneling nanotubes (TNTs) facilitate intercellular communication, enabling the spread of calcium currents and promoting invasion. The neuronal niche in the TME plays a crucial role in glioma invasion, with glioma cells forming synapses with neurons to enhance proliferation and invasion. Neuronal activity through AMPA receptors increases microtube branching and invasion speed. Paracrine factors released by neurons also promote glioma growth by activating signaling pathways that enhance tumor cell proliferation and invasion. The extracellular matrix (ECM) supports GBM invasion by providing a scaffold for cell migration. Components like hyaluronan, osteopontin, and fibronectin facilitate tumor cell infiltration. The vascular niche also contributes to GBM invasion by promoting tumor cell migration along blood vessels. Astrocytes support invasion by releasing factors that promote tumor growth and mesenchymal transformation. The immune microenvironment, including microglia, neutrophils, and myeloid cells, plays a role in GBM invasion by secreting factors that enhance tumor cell migration and dissemination. Therapeutic targeting of GBM invasion mechanisms is an important area of research. Molecular targeting strategies, such as inhibiting gap junctions and microtubules, have shown promise in reducing tumor growth and enhancing the effectiveness of chemoradiotherapy. Antiepileptic drugs, such as perampanel, have been investigated for their ability to inhibit neuron-tumor cell crosstalk and reduce glioma invasion. These findings highlight the complex interplay between tumor cells and their microenvironment in GBM progression and underscore the need for targeted therapies to combat this aggressive cancer.This review explores the intrinsic and microenvironmental factors driving glioblastoma (GBM) invasion. GBM is a highly aggressive brain tumor with poor prognosis due to its invasive nature and recurrence. Recent single-cell studies have revealed molecular mechanisms enabling glioma cells to invade normal brain tissue. The review discusses intrinsic biological drivers of tumor cell invasion, including interactions between tumor cells and the tumor microenvironment (TME). It highlights the role of the neuronal niche in the TME, which contributes to glioma growth and invasion. The mechanisms of invasion promoted by astrocytes and immune cells are also addressed. The review also covers current literature on therapeutic targeting of invasion mechanisms. GBM cells exhibit varying invasive and proliferative capacities, with different cell states contributing to tumor progression. Tumor microtubes (TMs) and tunneling nanotubes (TNTs) facilitate intercellular communication, enabling the spread of calcium currents and promoting invasion. The neuronal niche in the TME plays a crucial role in glioma invasion, with glioma cells forming synapses with neurons to enhance proliferation and invasion. Neuronal activity through AMPA receptors increases microtube branching and invasion speed. Paracrine factors released by neurons also promote glioma growth by activating signaling pathways that enhance tumor cell proliferation and invasion. The extracellular matrix (ECM) supports GBM invasion by providing a scaffold for cell migration. Components like hyaluronan, osteopontin, and fibronectin facilitate tumor cell infiltration. The vascular niche also contributes to GBM invasion by promoting tumor cell migration along blood vessels. Astrocytes support invasion by releasing factors that promote tumor growth and mesenchymal transformation. The immune microenvironment, including microglia, neutrophils, and myeloid cells, plays a role in GBM invasion by secreting factors that enhance tumor cell migration and dissemination. Therapeutic targeting of GBM invasion mechanisms is an important area of research. Molecular targeting strategies, such as inhibiting gap junctions and microtubules, have shown promise in reducing tumor growth and enhancing the effectiveness of chemoradiotherapy. Antiepileptic drugs, such as perampanel, have been investigated for their ability to inhibit neuron-tumor cell crosstalk and reduce glioma invasion. These findings highlight the complex interplay between tumor cells and their microenvironment in GBM progression and underscore the need for targeted therapies to combat this aggressive cancer.