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A combinatorial transcription factor screening platform for immune cell reprogramming

Kurochkin, Ilia LU ; Altman, Abigail R. LU orcid ; Caiado, Inês LU ; Pértiga-Cabral, Diogo LU ; Halitzki, Evelyn LU ; Minaeva, Mariia ; Zimmermannová, Olga LU ; Henriques-Oliveira, Luís LU ; Klein, Dominik and Nair, Malavika LU , et al. (2026) In Cell systems 17(1).
Abstract

Direct reprogramming of immune cells holds promise for immunotherapy but is constrained by limited knowledge of transcription factor (TF) networks. Here, we developed REPROcode, a combinatorial single-cell screening platform to identify TF combinations for immune cell reprogramming. We first validated REPROcode by inducing type-1 conventional dendritic cells (cDC1s) with multiplexed sets of 9, 22, and 42 factors. With cDC1-enriched TFs, REPROcode enabled identification of optimal TF stoichiometry, fidelity enhancers, and regulators of cDC1 states. We then constructed an arrayed lentiviral library of 408 barcoded immune TFs to explore broader reprogramming capacity. Screening 48 TFs enriched in dendritic cell subsets yielded myeloid and... (More)

Direct reprogramming of immune cells holds promise for immunotherapy but is constrained by limited knowledge of transcription factor (TF) networks. Here, we developed REPROcode, a combinatorial single-cell screening platform to identify TF combinations for immune cell reprogramming. We first validated REPROcode by inducing type-1 conventional dendritic cells (cDC1s) with multiplexed sets of 9, 22, and 42 factors. With cDC1-enriched TFs, REPROcode enabled identification of optimal TF stoichiometry, fidelity enhancers, and regulators of cDC1 states. We then constructed an arrayed lentiviral library of 408 barcoded immune TFs to explore broader reprogramming capacity. Screening 48 TFs enriched in dendritic cell subsets yielded myeloid and lymphoid phenotypes and enabled the construction of a TF hierarchy map to guide immune reprogramming. Finally, we validated REPROcode's discovery power by inducing natural killer (NK)-like cells. This study deepens our understanding of immune transcriptional control and provides a versatile toolbox for engineering immune cells to advance immunotherapy.

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publishing date
type
Contribution to journal
publication status
published
subject
keywords
antigen-presenting cells, barcoding, cellular reprogramming, combinatorial screening, dendritic cells, innate lymphoid cells, machine learning, transcription factor, transcriptional hierarchy
in
Cell systems
volume
17
issue
1
article number
101457
publisher
Cell Press
external identifiers
  • pmid:41539305
  • scopus:105027763344
ISSN
2405-4712
DOI
10.1016/j.cels.2025.101457
language
English
LU publication?
yes
id
5b54a2bb-f16f-45dd-997a-144f44b7f53a
date added to LUP
2026-02-19 15:07:29
date last changed
2026-02-20 03:14:29
@article{5b54a2bb-f16f-45dd-997a-144f44b7f53a,
  abstract     = {{<p>Direct reprogramming of immune cells holds promise for immunotherapy but is constrained by limited knowledge of transcription factor (TF) networks. Here, we developed REPROcode, a combinatorial single-cell screening platform to identify TF combinations for immune cell reprogramming. We first validated REPROcode by inducing type-1 conventional dendritic cells (cDC1s) with multiplexed sets of 9, 22, and 42 factors. With cDC1-enriched TFs, REPROcode enabled identification of optimal TF stoichiometry, fidelity enhancers, and regulators of cDC1 states. We then constructed an arrayed lentiviral library of 408 barcoded immune TFs to explore broader reprogramming capacity. Screening 48 TFs enriched in dendritic cell subsets yielded myeloid and lymphoid phenotypes and enabled the construction of a TF hierarchy map to guide immune reprogramming. Finally, we validated REPROcode's discovery power by inducing natural killer (NK)-like cells. This study deepens our understanding of immune transcriptional control and provides a versatile toolbox for engineering immune cells to advance immunotherapy.</p>}},
  author       = {{Kurochkin, Ilia and Altman, Abigail R. and Caiado, Inês and Pértiga-Cabral, Diogo and Halitzki, Evelyn and Minaeva, Mariia and Zimmermannová, Olga and Henriques-Oliveira, Luís and Klein, Dominik and Nair, Malavika and Oliveira, Daniel and Cajal, Laura Rabanal and Knittel, Ramin and Feick, Cora and Ringnér, Markus and Martin, Marcel and Cirovic, Branko and Pires, Cristiana F. and Rosa, Fabio F. and Sitnicka, Ewa and Theis, Fabian J. and Pereira, Carlos Filipe}},
  issn         = {{2405-4712}},
  keywords     = {{antigen-presenting cells; barcoding; cellular reprogramming; combinatorial screening; dendritic cells; innate lymphoid cells; machine learning; transcription factor; transcriptional hierarchy}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Cell Press}},
  series       = {{Cell systems}},
  title        = {{A combinatorial transcription factor screening platform for immune cell reprogramming}},
  url          = {{http://dx.doi.org/10.1016/j.cels.2025.101457}},
  doi          = {{10.1016/j.cels.2025.101457}},
  volume       = {{17}},
  year         = {{2026}},
}