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.