{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T05:42:29Z","timestamp":1761198149545,"version":"build-2065373602"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T00:00:00Z","timestamp":1761177600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>HOXA5 (homeobox A5) exhibits context-dependent roles in cancer, but its pan-cancer spatial immune regulatory functions and therapeutic potential remain poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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\u20134.89, p &amp;lt; 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 &amp;lt; 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1677713","type":"journal-article","created":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T05:38:08Z","timestamp":1761197888000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["HOXA5-mediated spatial remodeling of tumor-immune interfaces across cancers promotes AML 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