HES6 is a bHLH transcription factor that functions as a modulator of Notch signaling, primarily by suppressing HES1-mediated transcriptional repression and promoting cell differentiation 1. Unlike canonical HES proteins, HES6 does not directly repress transcription but instead sequesters other HES proteins, inhibiting their repressor activity and allowing differentiation-promoting genes to be expressed 1. This mechanism facilitates neurogenesis by enabling proneural factors like ASCL1 to promote differentiation 1. HES6 is expressed during normal development in epithelial differentiation pathways, including airway mucociliary differentiation where it marks deuterosomal precursors of multiciliated cells 2, and in hematopoiesis where it supports differentiation into erythroid, lymphoid, and dendritic cell lineages 3. In disease, HES6 expression is significantly dysregulated: it is the most glioma-specific gene identified in large-scale analyses and supports glioma cell proliferation and migration 4. In uveal melanoma, HES6 drives an invasive, metastatic phenotype and is a validated therapeutic target, as HES6 depletion impairs proliferation, migration, and metastatic dissemination 5. HES6 is also upregulated in small cell lung cancer, particularly as a Notch pathway inhibitor in neuroendocrine tumors 6. These findings identify HES6 as both a critical developmental regulator and an emerging oncogenic driver in multiple cancer types.