Homeobox genes in endocrine tumorigenesis: mechanisms, tumor microenvironment interaction, and therapeutic potential

The homeobox (HOX) gene family is a highly conserved group of transcription factors, important for embryonic patterning, positional identity, and lineage commitment. Although many HOX genes are largely silenced in adult endocrine tissues, emerging evidence suggests that their aberrant reactivation contributes to tumorigenic processes in certain endocrine neoplasms, such as thyroid cancer and adrenocortical carcinoma. This reactivation affects cell differentiation, proliferation, and lineage plasticity. Mechanistically, HOX proteins govern transcriptional networks involved in cell fate determination, epithelial-mesenchymal transition, metabolic reprogramming, and chromatin remodeling. They also interact with key signaling pathways, including MAPK, PI3K-Akt, TGF-β, and JAK-STAT. Beyond direct tumor cell functions, HOX genes shape the tumor microenvironment by regulating angiogenesis, immune cell recruitment, and extracellular matrix remodeling. These processes, in turn, facilitate tumor progression and therapeutic resistance. Given their context-specific expression patterns and epigenetic regulation, HOX genes show promise as biomarkers for diagnosis, prognosis, and treatment response. Therapeutic strategies targeting HOX signaling, including HOX-PBX inhibition, epigenetic modulation, and RNA-based technologies, offer new therapeutic avenues, although challenges related to specificity, delivery, and functional redundancy remain. A deeper mechanistic understanding of HOX-driven networks will aid the development of innovative biomarkers and therapies, thereby advancing precision medicine in endocrine oncology.