TopBP1 orchestrates PU.1–IRF8 transcriptional programming of dendritic cell differentiation and Flt3L-driven tumor immunity

Abstract DNA topoisomerase II-binding protein 1 (TopBP1) plays a critical role in V(D)J recombination and DNA damage repair during B and T cell development. However, its role in the development of conventional dendritic cells (cDCs) remains unexplored. Mice with DC-specific depletion of TopBP1 (TopBP1 cKO ) exhibited accelerated tumor progression due to impaired anti-tumor immunity, which was characterized by cDC deficiency and pre-DC accumulation. The cDC deficiency observed in TopBP1 cKO mice was not attributable to cell death resulting from accumulated DNA damage during DC development. Notably, Flt3 ligand (Flt3L)-mediated tumor immunotherapy was ineffective in TopBP1 cKO tumor-bearing mice. Here we demonstrate that TopBP1 is required not only for the steady-state differentiation of total cDCs, including both cDC1 and cDC2, but also for the terminal differentiation of XCR1 − CD24⁺ emergency progenitors (CD11c⁺cKit⁺) into XCR1⁺CD24⁺ cDC1s in response to Flt3L. Furthermore, TopBP1 was found to be essential for the function of the PU.1–IRF8 heterodimeric transcription factor complex, which is critical for cDC lineage specification. TopBP1 directly binds to this complex and facilitates the transcription of downstream target genes required for cDC development. These findings establish TopBP1 as a pivotal regulator of both steady-state and Flt3L-driven emergency cDC differentiation, particularly in guiding emergency progenitors into functional cDC1s. Our study highlights the previously unrecognized role of TopBP1 as a co-regulator of lineage-defining transcription factors and as a determinant of Flt3L-mediated anti-tumor efficacy.