HOXB9 drives tumor progression through dual functions: Remodeling the fibroblast microenvironment and mediating radioresistance

HOXB9 is a homeobox transcription factor aberrantly expressed in solid tumors and linked to poor prognosis, but its functions in the tumor microenvironment (TME) and therapy resistance are not fully understood. This study aimed to elucidate the oncogenic role of HOXB9, its impact on the TME, and its contribution to radioresistance. Pan-cancer expression and prognostic analyses were performed using databases including TCGA. Correlation between HOXB9 expression and cancer-associated fibroblast (CAF) infiltration was assessed using seven algorithms: TIMER, CIBERSORT, CIBERSORT-ABS, EPIC, QUANTISEQ, XCELL, and MCPCOUNTER. siRNA knockdown, cellular functional assays, conditioned medium treatment, and ELISA were employed to validate the effects of HOXB9 on malignant phenotypes, CAF activation, and IL-6 secretion in lung and breast cancer cells. Clonogenic assays were used to evaluate radiosensitivity. Single-cell and spatial transcriptomic data were integrated to dissect its expression heterogeneity. HOXB9 was significantly upregulated in multiple cancers, including lung adenocarcinoma and breast cancer, and its high expression correlated with poor patient prognosis and increased CAF infiltration. HOXB9 knockdown suppressed tumor cell proliferation, migration, and invasion, and reduced IL-6 secretion in conditioned medium, thereby attenuating CAF activation and migration; exogenous IL-6 supplementation partially rescued this effect. HOXB9 knockdown significantly sensitized tumor cells to X-ray irradiation. Single-cell and spatial analyses revealed that HOXB9 was enriched in malignant epithelial cells and CAFs and predominantly localized in the tumor core. HOXB9 functions as a multifunctional oncogene with three distinct roles: it drives malignant phenotypes in tumor cells, promotes CAF activation through paracrine IL-6 signaling to remodel the tumor microenvironment, and confers radioresistance. These findings support HOXB9 as a potential prognostic biomarker and therapeutic target for radiosensitization.