GLI3 in cancer: a context-dependent regulator with diagnostic, prognostic, and therapeutic potential

Malignant tumors remain a major global health burden, creating an urgent need for biomarkers and therapeutic targets that can improve diagnosis, prognostic stratification, and treatment. This review focuses on glioma-associated oncogene family zinc finger 3 (GLI3), a context-dependent transcription factor in the Hedgehog signaling pathway.

We integrated current evidence on GLI3 isoform processing, including the full-length activator GLI3A and the cleaved repressor GLI3R, as well as canonical and non-canonical regulatory mechanisms and the functional consequences of altered GLI3 signaling across diverse tumor types. The analysis revealed that GLI3 exerts both oncogenic and tumor-suppressive effects in a highly context-dependent manner. These effects are governed by the balance between GLI3A and GLI3R, tumor-specific signaling networks, and microenvironmental influences. Dysregulated GLI3 signaling is associated with epithelial-mesenchymal transition, cancer stem cell maintenance, immune remodeling, and therapeutic resistance. Moreover, GLI3 expression and isoform patterns show promise as diagnostic, prognostic, and susceptibility biomarkers. Emerging therapeutic strategies target GLI3 through indirect modulation, direct inhibition, or combination approaches. These findings highlight the potential clinical utility of GLI3.

This review identifies GLI3 as a pivotal regulator of tumor biology and highlights its potential as a promising target for precision oncology. Key challenges for future research include the development of isoform-specific detection methods, clarification of non-canonical regulatory mechanisms, and improved translational validation.