Glioblastoma is the most aggressive and lethal cancer of the central nervous system, presenting substantial treatment challenges. The current standard treatment, which includes surgical resection followed by temozolomide and radiation, offers limited success. While immunotherapies, such as immune checkpoint inhibitors, have proven effective in other cancers, they have not demonstrated significant efficacy in GBM. Emerging research highlights the pivotal role of tumor-associated macrophages (TAMs) in supporting tumor growth, fostering treatment resistance, and shaping an immunosuppressive microenvironment. Preclinical studies show promising results for therapies targeting TAMs, suggesting potential in overcoming these barriers. TAMs consist of brain-resident microglia and bone marrow-derived macrophages, both exhibiting diverse phenotypes and functions within the tumor microenvironment. This review delves into the origin, heterogeneity, and functional roles of TAMs in GBM, underscoring their dual roles in tumor promotion and suppression. It also summarizes recent progress in TAM-targeted therapies, which may, in combination with other treatments like immunotherapy, pave the way for more effective and personalized strategies against this aggressive malignancy.

Interferon-gamma (IFNG) has profound impacts on tumor-immune interaction and is of great clinical significance for multiple cancers. Exploring the role of IFNG in glioblastoma (GBM) may optimize the current treatment paradigm of this disease. Here, multi-dimensional data of 429 GBM samples were collected. Various bioinformatics algorithms were employed to establish a gene signature that characterizes immunological features, genomic alterations, and clinical characteristics associated with the IFNG response. In this way, a novel IFNG-related gene signature (IFNGrGS, including TGFBI, IL4I1, ACP5, and LUM) has been constructed and validated. Samples with increased IFNGrGS scores were characterized by increased neutrophil and macrophage infiltration and exuberant innate immune responses, while the activated adaptive immune response may be frustrated by multiple immunosuppressive mechanisms. Notably, the IFNG pathway as well as its antagonistic pathways including IL4, IL10, TGF-beta, and VEGF converged on the expression of immune checkpoints. Besides, gene mutations involved in the microenvironment were associated with the IFNGrGS-based stratification, where the heterogeneous prognostic significance of EGFR mutation may be related to the different degrees of IFNG response. Moreover, the IFNGrGS score had solid prognostic value and the potential to screen ICB and radiotherapy sensitive populations. Collectively, our study provided insights into the role of IFNG on the GBM immune microenvironment and offered feasible information for optimizing the treatment of GBM.

N6-methyladenosine (m6A) RNA methylation, the most common form of mRNA modification and regulated by the m6A RNA methylation regulators (“writers,” “erasers,” and “readers”), has been reported to be associated with the progression of the malignant tumor. However, its role in glioblastoma (GBM) has been poorly known. This study aimed to identify the expression, potential functions, and prognostic values of m6A RNA methylation regulators in GBM. Here, we revealed that the 13 central m6A RNA methylation regulators were firmly related to the clinical and molecular phenotype of GBM. Taking advantage of consensus cluster analysis, we obtained two categories of GBM samples and found malignancy-related processes of m6A methylation regulators and compounds that specifically targeted the malignant processes. Besides, we also obtained a list of genes with poor prognosis in GBM. Finally, we derived a risk-gene signature with three selected m6A RNA methylation regulators, which allowed us to extend the in-depth study and dichotomized the OS of patients with GBM into high- and low-risk subgroups. Notably, this risk-gene signature could be used as independent prognostic markers and accurate clinicopathological parameter predictors. In conclusion, m6A RNA methylation regulators are a type of vital participant in the malignant progression of GBM, with a critical potential in the prognostic stratification and treatment strategies of GBM.

Approximately 90% of glioblastoma recurrences occur in the peritumoral brain zone (PBZ), while the spatial heterogeneity of the PBZ is not well studied. In this study, two PBZ tissues and one tumor tissue sample are obtained from each patient via preoperative imaging. We assess the microenvironment and the characteristics of infiltrating immune/tumor cells using various techniques. Our data indicate there are one or more regions with higher cerebral blood flow in PBZ, which we collectively name the “higher cerebral blood flow interface” (HBI). The HBI exhibited more neovascularization than the “lower cerebral blood flow interfaces” (LBI). The HBI tend to have increased infiltration of macrophages and T lymphocytes infiltration compared with that in LBI. There are more tumor cells in the HBI than in LBI, with substantial differences in the gene expression profiles of these tumor cells. HBI may be the key area of PBZ-targeting therapy after surgical resection.

Osteosarcoma (OS) is a type of malignant primary bone cancer, which is highly aggressive and occurs more commonly in children and adolescents. Thus, novel potential drugs and therapeutic methods are urgently needed. In the present study, we aimed to elucidate the effects and mechanism of melatonin on OS cells to provide a potential treatment strategy for OS. The cell survival rate, cell viability, proliferation, migration, invasion and metastasis were examined by trypan blue assay, MTT, colony formation, wound healing, transwell invasion and attachment/detachment assay, respectively. The expression of relevant lncRNAs in OS cells was determined by real‐time qPCR analysis. The functional roles of lncRNA JPX in OS cells were further examined by gain and loss of function assays. The protein expression was measured by western blot assay. Melatonin inhibited the cell viability, proliferation, migration, invasion and metastasis of OS cells (Saos‐2, MG63 and U2OS) in a dose‐dependent manner. Melatonin treatment significantly downregulated the expression of lncRNA JPX in Saos‐2, MG63 and U2OS cells. Overexpression of lncRNA JPX into OS cell lines elevated the cell viability and proliferation, which was accompanied by the increased metastasis. We also found that melatonin inhibited the OS progression by suppressing the expression of lncRNA JPX via regulating the Wnt/β‐catenin pathway. Our results suggested that melatonin inhibited the biological functions of OS cells by repressing the expression of lncRNA JPX through regulating the Wnt/β‐catenin signalling pathway, which indicated that melatonin might be applied as a potentially useful and effective natural agent in the treatment of OS.

Photodynamics therapy (PDT) induces tumor cell death through oxidative stress and is closely associated with the expression of hypoxia inducible factor-1a (HIF1a), which activates multiple downstream survival signaling pathways. Therefore, the purpose of this study was to investigate the expression levels of HIF1a proteins in PDT-treated GBM cells and to determine whether inhibition of HIF1a reduces survival signals to enhance the efficacy of PDT. PDT combined with Acriflavine (ACF, PA) decreased the expression of HIF1a and regulated the downstream expression of GLUT-1, GLUT-3, HK2 and other gluconeogenic pathway proteins. PA group significantly suppressed tumor growth to improve the efficacy of PDT. We first performed the correlation of HIF1a, GLUT-1, GLUT-3, and HK2, and quantified the expression of HIF1a on tumor grades and IDH mutation classification by TCGA and CGGA databases. Then, we used immunohistochemistry method to detect four gene expression levels in human GBM tissues. Besides, we examined the effects of different treatments on the proliferation, migration and invasion ability of GBM cell lines by CCK8, wound healing and transwell assays. ACF, a HIF1a/HIF1β dimerization inhibitor, was used to evaluate its adjuvant effect on the efficacy of PDT. HIF1a is activated in GBM cell lines and contributes to the survival of tumor cells after PDT in vitro and in vivo. PA group inhibited HIF1a expression and improved PDT efficacy in the treatment of recalcitrant GBM.