Extracellular Ubiquitin Drives M2 Macrophage Polarization in Multiple Myeloma Through JAK1/STAT3‐mediated Transcriptional Activation of CXCR4

Macrophage polarization engenders an immunosuppressive microenvironment, thereby facilitating the survival and epithelial‐mesenchymal transition (EMT)‐like changes of malignant plasma cells. Ubiquitin (Ub), a short polypeptide predominantly involved in proteasome‐mediated protein degradation, has been detected extracellularly in body fluids. In certain diseases, it exerts immune‐regulatory functions, including the modulation of macrophage polarization. Nevertheless, its immune‐regulatory role in multiple myeloma (MM) remains undetermined. This study investigated the role of extracellular ubiquitin (eUb) in macrophage polarization and MM progression. We demonstrated that serum eUb levels were significantly higher in MM patients than in healthy volunteers. Elevated eUb levels were closely associated with a poor prognosis in MM patients. Exposure to eUb induced M2 macrophage polarization, which in turn promoted MM cell proliferation and EMT via the CXCR4/JAK1/STAT3 pathway. Notably, STAT3 was identified as a transcription factor that directly binds to the CXCR4 promoter, enhancing its expression and establishing a positive‐feedback loop. Collectively, eUb promotes MM cell proliferation and EMT‐like changes by driving M2 macrophage polarization through activation of the CXCR4/JAK1/STAT3 positive‐feedback pathway. These findings underscore the pathological significance of eUb in the MM tumor microenvironment and suggest that targeting this pathway may provide novel therapeutic strategies for MM.