Dendritic cells (DCs) are central orchestrators of antitumor immunity, yet their role in immune surveillance at preneoplastic stages remains largely unexplored. Here, we investigated the contribution of conventional type 1 DCs (cDC1) to early immune detection of preneoplastic lesions in a unique mouse model of spontaneous triple-negative breast cancer (TNBC), the BLG-Cre; Brca1^f/f; p53^+/- model, which recapitulates the genetic heterogeneity and sequential stages of human breast tumorigenesis with an intact immune system.

Using single-cell RNA sequencing (scRNA-seq) of over 120,000 cells, including 15,000 DCs, across healthy, preneoplastic and tumor stages, combined with spatial transcriptomics (Xenium, 10X Genomics), we first characterized emerging preneoplastic cells. InferCNV analysis of luminal epithelial cells identified a cluster of 450 preneoplastic cells displaying intermediate copy number variation profiles. Their transcriptomic signature enabled precise in situ localization within adenosis/hyperplasia areas, confirmed by anatomopathological analyses.

Within the cDC1 compartment, we identified a distinct subpopulation strongly expressing Cxcl9, significantly enriched at the preneoplastic stage. Trajectory analyses suggest these CXCL9⁺ cDC1 represent precursors of migratory CCR7⁺ cDC1, known to prime tumor-specific T cells in draining lymph nodes. Spatial transcriptomics confirmed their physical proximity with preneoplastic cells and T lymphocytes, supporting a role for the CXCL9/CXCR3 axis in local T cell recruitment.

As a preliminary finding, ligand-receptor interaction analyses suggest that TNFα, overexpressed by preneoplastic cells, may drive CXCL9⁺ cDC1 activation through TNF signaling, and promote their subsequent differentiation into CCR7⁺ cDC1. These results warrant further functional validation.

Collectively, these data support a model in which CXCL9⁺ cDC1 represent a specialized functional state acting as early sentinels to initiate adaptive antitumor immunity. These findings open new perspectives for harnessing innate immune surveillance in high-risk patients and improving immunotherapy strategies in TNBC.