Yu Wanli, Tang Wenting, Lin Wei, Jiang Ling, Xiang Yuyang, Li Yinyin, Zhou Yang, Chen Yuyang, Zhao Wenli, Zhu Yihan, Wei Xiaolei, Hu Yu, Bi Enguang
Department of Biochemistry and Molecular Biology, School of Basic Medical, Southern Medical University, Guangzhou 510515, China.
Division of Nephrology, Nanfang Hospital, Southern Medical University, State Key Laboratory of Multi-organ Injury Prevention and Treatment, National Clinical Research Center for Kidney Disease, Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, Guangdong 510515, China.
Mol Ther Oncol. 2025 May 14;33(2):200992. doi: 10.1016/j.omton.2025.200992. eCollection 2025 Jun 18.
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 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. , 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.
多发性骨髓瘤（MM）仍然是一种无法治愈的恶性肿瘤，其特征是恶性浆细胞增殖以及骨髓微环境内的显著失调。浆细胞样树突状细胞（pDC）在MM的免疫格局中发挥关键作用，常被MM细胞利用来支持肿瘤进展。在本研究中，我们通过对2000种小分子药物进行高通量筛选，确定视黄酸（RA）是pDC功能的有效调节剂。RA在CpG或瑞喹莫德刺激下显著增强pDC分泌干扰素（IFN）-α的能力，逆转MM诱导的IFN-α分泌抑制。机制上，RA上调pDC中Toll样受体（TLR）7/9的表达，放大TLR7/9激动剂诱导的IFN-α产生，并增强视黄酸诱导基因Ⅰ（RIG-Ⅰ）样信号传导和IFN刺激基因表达。此外，RA与CpG或瑞喹莫德联合使用可显著提高荷瘤小鼠的生存率，当RA、瑞喹莫德和硼替佐米联合使用时，观察到更大的生存益处。这些发现表明，RA可使pDC恢复活力，从而在临床前模型中更好地控制MM生长，为开发更有效的MM治疗方法提供了新的见解。
