Bone Marrow Microenvironment Drives Mature Neutrophil to a CD83 + Pro‐Tumor State in Multiple Myeloma

ABSTRACT Neutrophils are the most abundant immune cells in bone marrow (BM); their differentiation, maturation, and clearance are tightly regulated by the BM microenvironment. Multiple myeloma (MM) is a malignant plasma cell disorder that leads to multi‐organ damage, including BM disruption, which may subsequently affect resident neutrophils. The present study was designed to systematically characterize BM neutrophils in MM, to advance the understanding of their potential biological roles in disease initiation and progression, and to identify potential neutrophil‐based biomarkers of clinical relevance. Firstly, developmental profiling of BM neutrophils via cytomorphology and flow cytometry revealed a pronounced enrichment of mature neutrophils in MM patients. Furthermore, single‐cell RNA sequencing (scRNA‐seq) was utilized to characterize the transcriptional heterogeneity of BM neutrophils, with particular focus on the mature subsets. This analysis revealed a disease‐specific subpopulation of CD83 + neutrophils exhibiting anti‐apoptotic and senescence‐like features. The prolonged lifespan of these cells likely facilitates a phenotypic shift toward an immunosuppressive state, as evidenced by the upregulation of multiple inhibitory molecules. Clinical data, integrated with flow cytometric and bioinformatic analyses, were further applied to investigate the pro‐tumor features of CD83 + neutrophils and to uncover their potential tumor‐promoting pathways. Notably, the abundance of CD83 + neutrophils correlates with adverse clinical features in MM patients. In conclusion, this study demonstrates that the MM BM microenvironment shapes the maturation trajectory of neutrophils, driving the emergence of a CD83 + senescence‐like and pro‐tumor neutrophil subset. This provides new insights into neutrophil‐based biomarkers for risk stratification and disease monitoring in MM.