Ferroptosis is a form of cell death characterized by non-apoptosis induced by small molecules in tumors. Studies have demonstrated that ferroptosis regulates the biological behaviors of tumors. Therefore, genes that control ferroptosis can be a promising candidate bioindicator in tumor therapy. Herein, functions of ferroptosis-related genes in glioma were investigated. We systematically assessed the relationship between ferroptosis-related genes expression profiles and prognosis in glioma patients based on The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) RNA sequencing datasets. Using the non-negative matrix factorization (NMF) clustering method, 84 ferroptosis-related genes in the RNA sequencing data were distinctly classified into two subgroups (named cluster 1 and cluster 2) in glioma. The least absolute shrinkage and selection operator (LASSO) was used to develop a 25 gene risk signature. The relationship between the gene risk signature and clinical features in glioma was characterized. Results show that the gene risk signature associated with clinical features can be as an independent prognostic indicator in glioma patients. Collectively, the ferroptosis-related risk signature presented in this study can potentially predict the outcome of glioma patients.

As a cold tumor, malignant glioma has strong immunosuppression and immune escape characteristics. The tumor microenvironment (TME) provides the “soil” for the survival of malignant tumors, and cancer-associated fibroblasts (CAFs) are the architects of matrix remodeling in TME. Therefore, CAFs have potent regulatory effects on the recruitment and functional differentiation of immune cells, whereby they synthesize and secrete numerous collagens, cytokines, chemokines, and other soluble factors whose interaction with tumor cells creates an immunosuppressive TME. This consequently facilitates the immune escape of tumor cells. Targeting CAFs would improve the TME and enhance the efficacy of immunotherapy. Thus, regulation of CAFs and CAFs-related genes holds promise as effective immunotherapies for gliomas. Here, by analyzing the Chinese Glioma Genome Atlas and the Cancer Genome Atlas database, the proportion of CAFs in the tumor was revealed to be associated with clinical and immune characteristics of gliomas. Moreover, a risk model based on the expression of CAFs-related six-gene for the assessment of glioma patients was constructed using the least absolute shrinkage and selection operator and the results showed that a high-risk group had a higher expression of the CAFs-related six-genes and lower overall survival rates compared with those in the low-risk group. Additionally, patients in the high-risk group exhibited older age, high tumor grade, isocitrate dehydrogenase wildtype, 1p/19q non-codeletion, O-6-methylguanine-DNA methyltransferase promoter unmethylation and poor prognosis. The high-risk subtype had a high proportion CAFs in the TME of glioma, and a high expression of immune checkpoint genes. Analysis of the Submap algorithm indicated that the high-risk patients could show potent response to anti-PD-1 therapy. The established risk prediction model based on the expression of six CAFs-related genes has application prospects as an independent prognostic indicator and a predictor of the response of patients to immunotherapy.

Glioblastoma (GBM) is the most common malignant craniocerebral tumor. The treatment of this cancer is difficult due to its high heterogeneity and immunosuppressive microenvironment. Ferroptosis is a newly found non-apoptotic regulatory cell death process that plays a vital role in a variety of brain diseases, including cerebral hemorrhage, neurodegenerative diseases, and primary or metastatic brain tumors. Recent studies have shown that targeting ferroptosis can be an effective strategy to overcome resistance to tumor therapy and immune escape mechanisms. This suggests that combining ferroptosis-based therapies with other treatments may be an effective strategy to improve the treatment of GBM. Here, we critically reviewed existing studies on the effect of ferroptosis on GBM therapies such as chemotherapy, radiotherapy, immunotherapy, and targeted therapy. In particular, this review discussed the potential of ferroptosis inducers to reverse drug resistance and enhance the sensitivity of conventional cancer therapy in combination with ferroptosis. Finally, we highlighted the therapeutic opportunities and challenges facing the clinical application of ferroptosis-based therapies in GBM. The data generated here provide new insights and directions for future research on the significance of ferroptosis-based therapies in GBM.

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It is widely thought that the tumor microenvironment (TME) provides the “soil” for malignant tumors to survive. Prior to metastasis, the interaction at the host site between factors secreted by primary tumors, bone-marrow-derived cells, with stromal components initiates and establishes a pre-metastatic niche (PMN) characterized by immunosuppression, inflammation, angiogenesis and vascular permeability, as well as lymphangiogenesis, reprogramming and organotropism. Ferroptosis is a non-apoptotic cell death characterized by iron-dependent lipid peroxidation and metabolic constraints. Ferroptotic cancer cells release various signal molecules into the TME to either suppress or promote tumor progression. This review highlights the important role played by ferroptosis in PMN, focusing on the relationship between ferroptosis and PMN characteristics, and discusses future research directions.