Targeting a Myeloid–Regulatory B Cell Network Reverses Immune Paralysis in Periprosthetic Joint Infections

ABSTRACT The localized immunosuppressive microenvironment is a primary driver of treatment failure and high recurrence in periprosthetic joint infection (PJI). Although this state of immune paralysis is critical to the persistence of infection, clinically applicable immunomodulatory strategies to reverse it remain lacking. Here, utilizing single‐cell RNA sequencing to delineate the immunosuppressive landscape of a murine PJI model, we identified a pivotal subset of polymorphonuclear myeloid‐derived suppressor cells (PMN‐MDSCs) characterized by high CXCR4 expression. Mechanistically, we reveal that these CXCR4 ⁺ PMN‐MDSCs interact with AHR ⁺ and TIM1 ⁺ regulatory B cells (Bregs) to sustain a robust immunosuppressive axis. Modulation of CXCR4 signaling reduced the secretion of immunosuppressive mediators, such as ARG1, and decreased Breg abundance, effectively disrupting this suppressive network. To translate these immunological insights into clinical practice, we employed drug screening and identified alendronate as a specific inhibitor of CXCR4 ⁺ PMN‐MDSCs that acts directly via the signal transducer and activator of transcription 3 (STAT3). In vivo evidence from multiple infection models, combining alendronate with vancomycin significantly enhanced bacterial clearance, reversed local immune paralysis, and profoundly promoted structural bone repair. These findings uncover a druggable CXCR4 ⁺ PMN‐MDSC‐Breg immune tolerance network, offering a highly translational immunomodulatory paradigm for overcoming persistent skeletal infections.