Macrophage migration inhibitory factor promotes immune evasion in multiple myeloma through myeloid-derived suppressor cell immunosuppression and major histocompatibility complex class I downregulation: implications for targeted therapy.

Macrophage migration inhibitory factor (MIF), derived from either tumor cells or the tumor microenvironment, promotes multiple myeloma (MM) progression by suppressing T cell-mediated antitumor responses. Here, we demonstrate that MIF drives immune evasion in MM through both TME-mediated and tumor-intrinsic mechanisms. In the TME, MIF promotes the expansion of myeloid-derived suppressor cells (MDSCs) and enhances the expression of immunosuppressive molecules, including CD84, PD-L1, and CD38, thereby augmenting MDSC-mediated immunosuppression and impairing T cell function. In MM cells, MIF suppresses the COPS5/STAT1/NLRC5 signaling axis, resulting in downregulation of the major histocompatibility complex class I (MHC-I) antigen presentation pathway and reduced T cell-mediated cytotoxicity against MM cells. Therapeutically, combined treatment with the MIF inhibitor 4-IPP and dexamethasone delayed MM progression and prolonged survival in a mouse MM model. In summary, our findings reveal MIF as a critical mediator of immune escape in MM and highlight the therapeutic potential of MIF-targeted strategies for MM treatment.