Type I Interferon Pathway Activation Disrupts Monocyte Maturation and Enhances Immune Evasion in Multiple Myeloma

Abstract Monocyte‐derived cells, including osteoclasts, dendritic cells, and macrophages, are key components of the immunosuppressive tumor microenvironment in multiple myeloma (MM). However, the mechanisms linking monocyte dysfunction to immune evasion remain incompletely understood. In this study, single‐cell RNA sequencing (scRNA‐seq) of peripheral blood (PB) and bone marrow (BM) monocytes was performed from healthy donors (HDs) and MM patients to generate a comprehensive single‐cell transcriptional map. Although PB and BM monocytes displayed comparable cellular compositions, MM monocytes exhibited marked transcriptional alterations, most prominently within the type I interferon (IFN) signaling pathway. Trajectory analyses revealed IFN‐driven disruptions in monocyte differentiation and developmental trajectories in both PB and BM compartments. Functional co‐culture assays demonstrated that activation of the type I IFN pathway enhanced MM cell proliferation, suggesting that IFN‐mediated monocyte reprogramming facilitates tumor progression. In an independent validation cohort, longitudinal sampling before and after induction therapy confirmed that anti‐myeloma treatment alleviated the excessive IFN response of BM monocytes. Collectively, these findings uncover a mechanistic link between aberrant IFN activation and monocyte dysregulation in MM, providing new insights into immune dysfunction and highlighting the IFN pathway as a potential therapeutic target to restore anti‐tumor immunity.