HOXA5-mediated spatial remodeling of tumor-immune interfaces across cancers promotes AML pathogenesis

HOXA5 (homeobox A5) exhibits context-dependent roles in cancer, but its pan-cancer spatial immune regulatory functions and therapeutic potential remain poorly understood.

We integrated multi-omics data from 33 cancer types (TCGA, n=11,096; GTEx, n=7,469; TISCH2; spatial transcriptomics) to characterize HOXA5 expression, genomic alterations, and immune interactions. Functional validation was performed in AML cell lines (U937, KG-1; n=3 biological replicates per experiment).

HOXA5 was significantly dysregulated across cancers, with elevated expression in AML and GBM, and reduced expression in BRCA and LUAD. In AML, high HOXA5 expression predicted poor overall survival (HR = 2.80, 95% CI: 1.60-4.89, p < 0.001) and was associated with FLT3/NPM1 mutations. Spatial transcriptomics revealed HOXA5+ malignant cells enhance fibroblast/endothelial crosstalk via IGFBP3-TMEM219. HOXA5 knockdown suppressed proliferation (p < 0.01) and induced G0/G1 arrest. Mechanistically, HOXA5 maintained AML through cholesterol biosynthesis and ECM remodeling. Mercaptopurine was identified as a potential therapeutic agent, and molecular docking predicted a potential stable interaction with HOXA5.

HOXA5 plays a dual role in solid versus hematologic malignancies and serves as a key spatial immune regulator. It is a robust prognostic biomarker and therapeutic target in AML, with mercaptopurine representing a promising repurposing candidate.