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. 2025 Aug 11;43(8):1442-1459.e10.
doi: 10.1016/j.ccell.2025.05.002. Epub 2025 May 29.

Microbial cancer immunotherapy reprograms hematopoiesis to enhance myeloid-driven anti-tumor immunity

Andrew W Daman  1 , Anthony C Antonelli  2 , Gil Redelman-Sidi  3 , Lucinda Paddock  4 , Shireen Khayat  5 , Mythili Ketavarapu  6 , Jin Gyu Cheong  7 , Leonardo F Jurado  8 , Anna Benjamin  9 , Song Jiang  10 , Dughan Ahimovic  1 , Victoria R Lawless  1 , Michael J Bale  1 , Oleg Loutochin  8 , Victor A McPherson  11 , Maziar Divangahi  8 , Rachel E Niec  12 , Dana Pe'er  13 , Eugene Pietzak  10 , Steven Z Josefowicz  14 , Michael S Glickman  15
Affiliations

Microbial cancer immunotherapy reprograms hematopoiesis to enhance myeloid-driven anti-tumor immunity

Andrew W Daman et al. Cancer Cell. .

Abstract

Mycobacterium bovis Bacillus Calmette-Guérin (BCG) is the vaccine against tuberculosis and an immunotherapy for bladder cancer. When administered intravenously, BCG reprograms bone marrow hematopoietic stem and progenitor cells (HSPCs), leading to heterologous protection against infections. Whether HSPC reprogramming contributes to the anti-tumor effects of BCG administered into the bladder is unknown. We demonstrate that BCG administered in the bladder colonizes the bone marrow and, in both mice and humans, reprograms HSPCs to alter and amplify myelopoiesis. BCG-reprogrammed HSPCs are sufficient to confer augmented anti-tumor immunity through production of neutrophils, monocytes, and dendritic cells that broadly remodel the tumor microenvironment, drive T cell-dependent anti-tumor responses, and synergize with checkpoint blockade. We conclude that bladder BCG acts systemically through hematopoiesis, highlighting the broad potential of HSPC reprogramming to enhance the innate drivers of T cell-dependent tumor immunity.

Keywords: BCG; bladder cancer; epigenetics; hematopoiesis; immunotherapy; innate immune memory; trained immunity; tumor immunity.

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Conflict of interest statement

Declaration of interests A.W.D., A.C.A., G.R.-S., S.Z.J., and M.S.G. declare that a patent (CRNU-P0029W0) has been submitted related to this work. M.S.G. declares equity and consulting fees from Vedanta biosciences and consulting fees from Fimbrion therapeutics. S.Z.J. is a co-founder of Epistemyx Inc.

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