Enhancing plasmacytoid dendritic cell functionality with all-trans retinoic acid for improved multiple myeloma therapy.

Multiple myeloma (MM) remains an incurable malignancy characterized by the proliferation of malignant plasma cells and significant dysregulation within the bone marrow microenvironment. Plasmacytoid dendritic cells (pDCs) play a crucial role in the immune landscape of MM, often being co-opted by MM cells to support tumor progression. In this study, we identified all-trans retinoic acid (RA) as a potent modulator of pDC function through a high-throughput screening of 2,000 small-molecule drugs. RA significantly enhances pDCs' capacity to secrete interferon (IFN)-α upon CpG or Resiquimod stimulation, reversing the MM-induced suppression of IFN-α secretion. Mechanistically, RA upregulates Toll-like receptor (TLR)7/9 expression in pDCs, amplifying TLR7/9 agonist-induced IFN-α production and enhancing retinoic acid-inducible gene Ⅰ (RIG-Ⅰ)-like signaling and IFN-stimulated gene expression. In vivo, RA combined with CpG or Resiquimod significantly improves the survival of MM-bearing mice, with even greater pro-survival benefits observed when RA, Resiquimod, and bortezomib are combined. These findings demonstrate that RA rejuvenates pDCs, leading to improved control of MM growth in preclinical models, offering novel insights into developing more effective MM therapies.