Glioblastoma (GBM) is characterized by its unique molecular features, such as self-renewal and tumorigenicity of glioma stem cells that promote resistance, largely resulting in treatment failure. Among the molecular alterations significant to GBM biology and treatment, mutations in isocitrate dehydrogenase (IDH) have assumed particular relevance. IDH-mutant and IDH-wild-type tumors exhibit significantly different metabolic characteristics, clinical behavior, and therapeutic sensitivities, making IDH status a critical determinant in determining prognosis and treatment strategies for GBM. In the context of cancer, chaperones were shown to promote tumor progression by supporting malignant cells over healthy ones. While heat shock proteins (HSPs) have long been implicated in the molecular mechanisms of tumor phenotype progression, recent attention has turned to CCT (chaperonin containing TCP1), orchestrating proteostasis. The chaperonin CCT is being explored as a diagnostic and therapeutic target in many cancers, including GBM, owing to its involvement in key oncogenic signaling pathways such as Wnt, VEGF, EGFR, and PI3K/AKT/mTOR. However, its role in the GBM-tricarboxylic acid (TCA) cycle cascade is still not well understood. Therefore, the present review highlights the potential role of the CCT complex in regulating hypoxia-inducible factor (HIF) activation by modulating enzymes responsive to metabolites derived from glucose metabolism and the TCA cycle in a manner dependent on oxygen availability and IDH mutation status.

Molecular chaperones, especially Heat Shock Proteins (HSPs), play complex, context-dependent roles in cancer, particularly in nervous system (NS) tumors like glioblastoma (GBM) and neuroblastoma (NB). They are often upregulated, promoting tumor growth, poor prognosis, and resistance to therapy and immune responses. This supports the potential of negative chaperonotherapy, aimed at inhibiting them. However, some studies suggest chaperones can also act as tumor suppressors in certain cancers, indicating that positive chaperonotherapy—enhancing or restoring their function—may be beneficial. For NS tumors, this latter area is still understudied. With emphasis on GBM and NB, in this review we address the potential of molecular chaperones, particularly HSPs, as therapeutic targets or agents. We discuss strategies to inhibit pro-tumorigenic chaperones as well as the underexplored potential of chaperone induction and immunomodulation. Ultimately, we examine the emerging use of pharmacological and chemical chaperones to improve treatment outcomes in these NS tumors. These strategies, whether applied alone or in combination, may offer significant benefits for GBM and NB, which are presently among the most aggressive and challenging tumors to manage.