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BCG\u2010derived heat shock protein 70 (BCG HSP70, Dnak) has previously been recognized only as an immune adjuvant, while its role in trained immunity remains unexplored. This study identifies Dnak as a safe, defined inducer that establishes durable central trained immunity through epigenetic and metabolic reprogramming of bone marrow hematopoietic stem cells, conferring protection against bacterial infection. In prostate cancer models, a single Dnak pre\u2010treatment significantly inhibits tumor growth\u2014an effect transferable via bone marrow transplantation and dependent on tumor\u2010associated macrophages. Mechanistically, Dnak\u2010trained macrophages exhibit enhanced glycolysis, mTOR\/HIF\u20101\u03b1 pathway activation, and M1\u2010like polarization. Notably, O\u2010GlcNAcylation emerges as a previously unrecognized regulator of trained immunity. Furthermore, combining Dnak\u2010induced trained immunity with a tumor vaccine achieves superior tumor control, reshapes the tumor microenvironment, and generates durable memory T cell responses upon rechallenge. These findings establish BCG HSP70 as a safe and effective protein\u2010based trained immunity inducer with translational potential for cancer immunotherapy.<\/jats:p>","DOI":"10.1002\/advs.76886","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T14:54:56Z","timestamp":1785941696000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["BCG HSP70 Reprograms Macrophages via Central Trained Immunity to Suppress Prostate Cancer"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9262-0036","authenticated-orcid":false,"given":"Peng","family":"Liu","sequence":"first","affiliation":[{"name":"Nankai University  Tianjin China"},{"name":"Department of Urology, Tianjin Institute of Urology The Second Hospital of Tianjin Medical University  Tianjin China"},{"name":"Tianjin Medical University General Hospital  Tianjin China"},{"name":"Haihe Laboratory of Sustainable Chemical 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