Glioma is the most common intracranial malignant tumor, and the current main standard treatment option is a combination of tumor surgical resection, chemotherapy and radiotherapy. Due to the terribly poor five-year survival rate of patients with gliomas and the high recurrence rate of gliomas, some new and efficient therapeutic strategies are expected. Recently, ferroptosis, as a new form of cell death, has played a significant role in the treatment of gliomas. Specifically, studies have revealed key processes of ferroptosis, including iron overload in cells, occurrence of lipid peroxidation, inactivation of cysteine/glutathione antiporter system Xc⁻ (xCT) and glutathione peroxidase 4 (GPX4). In the present review, we summarized the molecular mechanisms of ferroptosis and introduced the application and challenges of ferroptosis in the development and treatment of gliomas. Moreover, we highlighted the therapeutic opportunities of manipulating ferroptosis to improve glioma treatments, which may improve the clinical outcome.

Glioma is a malignant tumor of the central nervous system (CNS). Currently, effective treatment options for gliomas are still lacking. Neutrophils, as an important member of the tumor microenvironment (TME), are widely distributed in circulation. Recently, the discovery of cranial-meningeal channels and intracranial lymphatic vessels has provided new insights into the origins of neutrophils in the CNS. Neutrophils in the brain may originate more from the skull and adjacent vertebral bone marrow. They cross the blood-brain barrier (BBB) under the action of chemokines and enter the brain parenchyma, subsequently migrating to the glioma TME and undergoing phenotypic changes upon contact with tumor cells. Under glycolytic metabolism model, neutrophils show complex and dual functions in different stages of cancer progression, including participation in the malignant progression, immune suppression, and anti-tumor effects of gliomas. Additionally, neutrophils in the TME interact with other immune cells, playing a crucial role in cancer immunotherapy. Targeting neutrophils may be a novel generation of immunotherapy and improve the efficacy of cancer treatments. This article reviews the molecular mechanisms of neutrophils infiltrating the central nervous system from the external environment, detailing the origin, functions, classifications, and targeted therapies of neutrophils in the context of glioma.

Background: In the tumor immune microenvironment (TIME), triggering receptor expressed on myeloid cells 2 (trem2) is widely considered to be a crucial molecule on tumor-associated macrophages(TAMs). Multiple studies have shown that trem2 may function as an immune checkpoint in various malignant tumors, mediating tumor immune evasion. However, its specific molecular mechanisms, especially in glioma, remain elusive. Methods: Lentivirus was transfected to establish cells with stable knockdown of trem2. A Transwell system was used for segregated coculture of glioma cells and microglia. Western blotting, quantitative real-time polymerase chain reaction (qRT‒PCR), and immunofluorescence (IF) were used to measure the expression levels of target proteins. The proliferation, invasion, and migration of cells were detected by colony formation, cell counting kit-8 (CCK8), 5-ethynyl-2’-deoxyuridine (EdU) and transwell assays. The cell cycle, apoptosis rate and reactive oxygen species (ROS) level of cells were assessed using flow cytometry assays. The comet assay and tube formation assay were used to detect DNA damage in glioma cells and angiogenesis activity, respectively. Gl261 cell lines and C57BL/6 mice were used to construct the glioma orthotopic transplantation tumor model. Results: Trem2 was highly overexpressed in glioma TAMs. Knocking down trem2 in microglia suppressed the growth and angiogenesis activity of glioma cells in vivo and in vitro. Mechanistically, knockdown of trem2 in microglia promoted proinflammatory microglia and inhibited anti-inflammatory microglia by activating jak2/stat1 and inhibiting the NF-κB p50 signaling pathway. The proinflammatory microglia produced high concentrations of nitric oxide (NO) and high levels of the proinflammatory cytokines TNF-α, IL-6, and IL-1β, and caused further DNA damage and promoted the apoptosis rate of tumor cells. Conclusions: Our findings revealed that trem2 in microglia plays a significant role in the TIME of gliomas. Knockdown of trem2 in microglia might help to improve the efficiency of inhibiting glioma growth and delaying tumor progression and provide new ideas for further treatment of glioma.

Glioma is a common primary nervous system malignant tumor with poor overall cure rate and low survival rate, yet successful treatment still remains a challenge. Here, we demonstrated that amantadine (AMT) exhibits the powerful anti-glioma effect by promoting apoptosis and autophagy in vivo and in vitro. Mechanistically, amantadine induces a large amount of reactive oxygen species (ROS) accumulation in glioma cells, and then triggers apoptosis by destroying mitochondria. In addition, amantadine induces the initiation of autophagy and inhibits the fusion of autophagosome and lysosome, consequently performing an anti-glioma role. Taken together, our findings suggest that amantadine could be a promising anti-glioma drug that inhibits glioma cells by inducing apoptosis and autophagy, which may provide a novel potential treatment option for patients.