Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor, and it is associated with poor prognosis. Its characteristics of being highly invasive and undergoing heterogeneous genetic mutation, as well as the presence of the blood–brain barrier (BBB), have reduced the efficacy of GBM treatment. The emergence of a novel therapeutic method, namely, sonodynamic therapy (SDT), provides a promising strategy for eradicating tumors via activated sonosensitizers coupled with low-intensity ultrasound. SDT can provide tumor killing effects for deep-seated tumors, such as brain tumors. However, conventional sonosensitizers cannot effectively reach the tumor region and kill additional tumor cells, especially brain tumor cells. Efforts should be made to develop a method to help therapeutic agents pass through the BBB and accumulate in brain tumors. With the development of novel multifunctional nanosensitizers and newly emerging combination strategies, the killing ability and selectivity of SDT have greatly improved and are accompanied with fewer side effects. In this review, we systematically summarize the findings of previous studies on SDT for GBM, with a focus on recent developments and promising directions for future research.

Epidermal growth factor receptor variant III (EGFRvIII) confers growth advantage to glioblastoma multiforme (GBM) and is associated with significantly shorter survival in GBM patients. The interaction between tumor cells and macrophages plays a crucial role in tumor development, supporting angiogenesis, nurturing tumor stem cells, and promoting immune-suppressive TME. Therefore, elucidating the potential mechanisms by which EGFRvIII mutation in GBM cells regulates surrounding immune cells to drive tumor progression may provide new targets for precise immune therapy for specific GBM subtypes or genotypes. In this study, we found that EGFRvIII was the most common form of EGFR mutation, with an incidence rate of 22.13% in glioma patients and 33.3% in GBM patients. Mechanistically, we found for the first time that EGFRvIII-positive GBM secretes high levels of MDK via the ERK-c-Fos signaling pathway. Subsequently, GBM cell-secreted MDK drives macrophage polarization towards the M2 phenotype and secretion of the cytokine CXCL1 via activation of the macrophage surface receptor LRP1 and downstream pathways. In turn, these macrophages secrete CXCL1, which attracts immune-suppressive cells and TAMs to support GBM growth. In the intracranial glioma model, blocking MDK signaling pathway could inhibit macrophage polarization towards the M2 phenotype and tumor malignant progression. In summary, our study for the first time found that EGFRvIII-positive GBM can drive macrophage polarization towards M2 phenotype and secretion of immune-suppressive cytokine CXCL1 via the c-Fos-MDK-LRP1 signaling pathway, providing new targets for precise immune therapy for specific GBM subtypes or genotypes.

The S100 protein family consists of 25 members and share a common structure defined in part by the Ca²⁺ binding EF-hand motif. Multiple members' dysregulated expression is associated with progression, diagnosis and prognosis in a broad range of diseases, especially in tumors. They could exert wide range of functions both in intracellular and extracellular, including cell proliferation, cell differentiation, cell motility, enzyme activities, immune responses, cytoskeleton dynamics, Ca²⁺ homeostasis and angiogenesis. Gliomas are the most prevalent primary tumors of the brain and spinal cord with multiple subtypes that are diagnosed and classified based on histopathology. Up to now the role of several S100 proteins in gliomas have been explored. S100A8, S100A9 and S100B were highly expression in serum and may present as a marker correlated with survival and prognosis of glioma patients. Individual member was confirmed as a new regulator of glioma stem cells (GSCs) and a mediator of mesenchymal transition in glioblastoma (GBM). Additionally, several members up- or downregulation have been reported to involve in the development of glioma by interacting with signaling pathways and target proteins. Here we detail S100 proteins that are associated with glioma, and discuss their potential effects on progression, diagnosis and prognosis.

Glioma is the most prevalent type of primary brain tumor, and glioblastoma multiforme (GBM) is the highest and most deadly type of primary central nervous system (CNS) tumor, affecting a significant number of patients each year, with a median overall survival of approximately 14.6 months after diagnosis. Despite intensive treatment, nearly all GBM patients experience recurrence, with a 5-year survival rate of about 5%. The protective BBB and high tumor heterogeneity prevent the effective delivery of drugs, resulting in the treatment failure of various drugs. The emergence of nanometer-scale diagnosis and treatment methods has provided new promising approaches to overcome these difficulties. Thus, our review focuses on the development of BBB-crossing nanomedicine-enhanced chemotherapy and combined therapy applications for glioma. Meanwhile, we also reviewed the strategies to overcome the blood–brain barrier. Additionally, we discuss recent achievements in the area of brain tumor treatment with nanomedicine and the rational design approach, which will offer recommendations for anti-GBM nanomedicine development.