Spatial transcriptomics identifies immune-stromal niches associated with cancer in adult dermatomyositis.

Adult-onset dermatomyositis (DM) is an autoimmune inflammatory myopathy with distinct cutaneous manifestations and a strong association with malignancy. Through comparative analysis with cutaneous lupus erythematosus (CLE), our integrated spatial and single-cell transcriptomics analysis reveals unique immune and stromal niches associated with DM subtypes. We find that cancer-associated DM skin lesions are distinguished by the presence of dispersed immune infiltrates enriched with macrophages or organized lymphoid aggregates with dense B cell cores surrounded by CD4 + /CD8 + T cells, accompanied by preserved vascular architecture. In contrast, non-cancer-associated DM skin is characterized by dense myeloid cell infiltrates, harbouring elevated expression of IL1B and CXCL10 localizing near injured vascular endothelia. Cytokines produced by these myeloid infiltrates, together with local tissue hypoxia, trigger dramatic stromal remodelling, leading to loss of vascular-associated fibroblasts. In addition to the CXCL10+ myeloid signature, non-cancer-associated DM skin is characterized by specific cellular pairs: PD-L1-expressing mature dendritic cells enriched in immunoregulatory molecules (mregDC) and activated regulatory T cells (Treg) expressing NFKB2 and TNF receptors. While both DM and CLE show strong interferon signatures, DM uniquely displays IFNβ expression. Together, our study provides a comprehensive spatial mapping of immune and stromal cells in adult-onset DM.