Anchored screening identifies transcription factor blueprints underlying dendritic cell diversity and subset-specific anti-tumor immunity.
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Henriques-Oliveira L, Altman AR, Kurochkin I, Ascic E, Halitzki E, Matei AM, Pértiga-Cabral D, Ulmert I, Holst S, Nair MS, Cunha PP, Park SM, Vergani S, Kharas MG, Yuan J, Lahl K, Rosa FF, Pires CF, Pereira CF
Immunity 58 (10) 2419-2438.e13 [2025-10-14; online 2025-08-29]
Transcription factor cooperation is essential for specifying the heterogeneous dendritic cell (DC) lineages that orchestrate adaptive immunity, yet how it drives subset diversification remains poorly understood. Here, we employed a sequential anchored screen of 70 transcription factors using direct cellular reprogramming to identify regulators that specify type 2 conventional DCs (cDC2s) and plasmacytoid DCs (pDCs). We identified PU.1, IRF4, and PRDM1 as inducers of a pro-inflammatory cDC2B-like fate and SPIB, IRF8, and IKZF2 as mediators of an immature lymphoid DC program. Transcriptomic profiling linked these triads to lineage-specific signatures and demonstrated their requirement for subset identity. Mechanistically, lineage divergence was driven by chromatin co-engagement at subset-specific sites early in reprogramming. Functionally, reprogrammed DCs employed distinct immune mechanisms to elicit orthogonal anti-tumor responses in different tumor models. Collectively, our findings uncover transcriptional circuits that control DC diversification and pave the way to generate patient-tailored DC subsets for cancer immunotherapy.
Clinical Genomics Lund [Service]
PubMed 40885192
DOI 10.1016/j.immuni.2025.08.001
Crossref 10.1016/j.immuni.2025.08.001
pii: S1074-7613(25)00335-8