BCG HSP70 Reprograms Macrophages via Central Trained Immunity to Suppress Prostate Cancer

Trained immunity offers a promising yet clinically challenging strategy for cancer immunotherapy, as current inducers such as BCG pose safety concerns and their active components remain ill‐defined. BCG‐derived 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‐treatment significantly inhibits tumor growth—an effect transferable via bone marrow transplantation and dependent on tumor‐associated macrophages. Mechanistically, Dnak‐trained macrophages exhibit enhanced glycolysis, mTOR/HIF‐1α pathway activation, and M1‐like polarization. Notably, O‐GlcNAcylation emerges as a previously unrecognized regulator of trained immunity. Furthermore, combining Dnak‐induced 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‐based trained immunity inducer with translational potential for cancer immunotherapy.