Nuclear and membrane-bound hormone receptors in glioblastoma: Expression, functionality, and therapeutic implications

The 2021 WHO classification of brain tumors emphasizes integrating molecular features with histopathology, notably redefining astrocytoma and glioblastoma entities. Recent research underscores the influence of sex hormones in glioblastoma development and therapy response. This review focuses on the 5-year updated understanding of the role of nuclear and membrane receptors in glioblastoma biology and therapy. Notably, androgen receptor expression is linked to worse outcomes, but recent studies suggest androgen signaling might sustain anti-tumor immunity. Estrogen receptor subtypes, as well as nuclear or membrane progesterone receptors, show divergent roles. Beyond classical nuclear receptors, attention is paid to membrane-bound and G protein-coupled receptors (GPCRs), which regulate key pathways in glioblastoma progression. Among them, G protein-coupled membrane estrogen receptor, the G protein-coupled estrogen receptor, is gaining attention for its ability to modulate cell proliferation and tumor behavior. CXCR4, a chemokine receptor, is now seen as a critical driver of tumor growth and immune evasion. Cannabinoid receptors are also implicated in glioblastoma proliferation and drug resistance. Dopamine receptors, particularly DRD2 and DRD3, are emerging as regulators of glioblastoma stem cell maintenance and therapy resistance. Targeting hormone and GPCR-related pathways, especially considering sex-specific factors, offers promising avenues for developing personalized glioblastoma treatments and enhancing current therapy outcomes.