Abstract
BACKGROUND: HOXB5, a member of the homeobox (HOX) gene family. Its dysregulated expression has been increasingly reported across multiple human cancers, where it correlates with malignant progression and poor clinical outcomes. A concise synthesis of its regulatory networks and cancer-associated functions is therefore needed to clarify its biological and translational significance. MAIN BODY: This review summarizes the expression landscape of HOXB5 across diverse tumor types and delineates its key regulatory mechanisms, including noncoding RNAs, DNA methylation, histone modifications, phosphorylation events, HOX/PBX interactions, NPM1 mutations, RB1 loss, and single-nucleotide polymorphisms. Functionally, HOXB5 acts as a central regulatory node that integrates multiple signaling pathways to modulate cancer cell proliferation, migration, invasion, apoptosis, epithelial–mesenchymal transition (EMT), and remodeling of the tumor microenvironment. Notably, HOXB5 displays context-dependent dual functions in cancer, acting predominantly as an oncogene but serving as a tumor suppressor in specific settings. For example, HOXB5 can restrain tumor growth by driving B-cell conversion into tumor-specific T cells, while loss of the chromatin remodelers Arid4a/Arid4b reduces HOXB5 expression and may accelerate the progression of certain myeloid disorders to AML. CONCLUSIONS: HOXB5 functions as either an oncogene or a tumor suppressor in a context-dependent manner, and it holds substantial potential as a diagnostic, prognostic, and therapeutic target. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-025-07654-1.