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Updated: Jun 9, 2026
Advancements in the Metabolic Profiling of Three-Dimensional Brain Tumor Spheroids for Drug Screening
Published on: September 5, 2025
xCT modulation in gliomas: relevance to energy metabolism and tumor microenvironment normalization
Nic E Savaskan1, Ilker Y Eyüpoglu
1Institute of Cell Biology and Neurobiology, Center for Anatomy, CCM2, Charité-Medical School Berlin, D-10117 Berlin, Germany. savaskan@gmx.net
Abstract:
Several nutrient transporters impacting the glutathione/redox cycle regulation and cell proliferation have been identified in cancer, which render these transporters potential prime targets for cytotoxic anticancer therapy. One promising transporter is system X(c)(-), also known as xCT (SLC7a11), which is expressed in various cancers including primary malignant brain tumors (gliomas). An important biological feature of these transporters, and in particular of xCT is its specific modulation of the tumor microenvironment leading to growth advantage for cancer. Thus, tumor microenvironment shaping by xCT inhibition revealed a so far neglected hallmark of gliomas, i.e. tumor-induced neurotoxicity and its impact on the development of peritumoral brain swelling. This review here discusses available pharmacological tools for the tumor microenvironment normalization, in the context of perifocal edema and the Warburg effect and highlights the implications of such metabolic normalization approach in the design of new therapies.
Insights
System X(c)(-) (xCT) transporter inhibition normalizes the tumor microenvironment in gliomas. This approach targets tumor-induced neurotoxicity and brain swelling, offering new therapeutic strategies.
Area of Science:
- Oncology
- Neuroscience
- Biochemistry
Background:
- Nutrient transporters regulate cancer cell proliferation and redox balance.
- System X(c)(-) (xCT, SLC7a11) is upregulated in various cancers, including gliomas.
- xCT significantly influences the tumor microenvironment, promoting cancer growth.
Purpose of the Study:
- To review pharmacological strategies for normalizing the tumor microenvironment in gliomas.
- To highlight the role of xCT in tumor-induced neurotoxicity and peritumoral brain swelling.
- To discuss the implications of metabolic normalization for novel glioma therapies.
Main Methods:
- Literature review of pharmacological agents targeting nutrient transporters.
- Analysis of xCT's role in glioma pathobiology and the tumor microenvironment.
- Discussion of therapeutic strategies focusing on metabolic normalization.
Main Results:
- xCT inhibition modulates the tumor microenvironment, impacting glioma progression.
- Targeting xCT reveals tumor-induced neurotoxicity and peritumoral edema as key glioma hallmarks.
- Pharmacological normalization of the tumor microenvironment presents a promising therapeutic avenue.
Conclusions:
- Inhibition of xCT offers a strategy to normalize the glioma tumor microenvironment.
- Addressing tumor-induced neurotoxicity and edema via metabolic normalization is crucial for glioma treatment.
- Metabolic normalization approaches hold significant potential for developing new glioma therapies.
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