LILRB4 drives proinflammatory cytokine secretion in multiple myeloma to promote the immune-cell dysfunction via the generation of myeloid-derived suppressive cells

Abstract Recent advancements in the treatment of multiple myeloma (MM), including immunomodulatory agents, monoclonal antibodies, and T cell-redirecting therapies, have significantly improved patient outcomes. However, MM remains incurable. The interaction between MM cells and non-malignant cells within the immunosuppressive tumor immune microenvironment (TiME) plays a critical role in disease progression, but it has not been fully elucidated. Our previous study reported that myeloid-derived suppressor cells (MDSCs), dysfunctional dendritic cells (DCs), and tumor-promoting osteoclasts (OCs) are enriched in the bone marrow of myeloma patients and play critical roles in T cell dysfunction. However, the underlying mechanisms remain incompletely understood (Front Immunol. 2022). A myeloid inhibitory receptor, LILRB4, was identified as highly expressed in a super high-risk subgroup of MM cells by single-cell RNA sequencing of patient samples. LILRB4 expression facilitated the generation of monocytic MDSCs and was associated with poor outcomes in MM patients (Haematologica 2024 & 2025). These findings suggest a potential mechanism by which LILRB4 drives an immunosuppressive microenvironment through the induction of immunosuppressive myeloid cells. Here, we further observed a significant reduction in erythroid-lineage commitment in MM patients with high LILRB4 expression, and we explored its molecular and cellular impact on the interaction between myeloma cells and the tumor microenvironment (TME). We report that LILRB4 is highly expressed in MM and activates the SHP2/ERK/AP-1 signaling cascade, thereby enhancing the expression of AP-1-associated chemokines and promoting the transdifferentiation of erythroid cells into immunosuppressive erythroid-derived myeloid cells (EDMCs). Through in vivo and in vitro analyses, we demonstrate that CD45⁺ erythroid progenitor cells (EPCs) in the MM microenvironment lose their erythroid differentiation potential and instead transdifferentiate into EDMCs. This reprogramming is driven by elevated levels of CCL3 secreted by LILRB4⁺ MM cells. Compared with the control group, deletion of CCL3 significantly inhibited myeloma cell growth, increased peripheral blood hemoglobin levels, reduced EDMC proportions in the bone marrow, enhanced IFN-γ secretion by CD8⁺ T cells, decreased the frequency of regulatory T cells (Tregs), and reduced the proportion of macrophages. Additionally, the ratio of monocytic MDSCs (M-MDSCs), which preferentially differentiate into tumor-associated macrophages (TAMs), to granulocytic MDSCs (G-MDSCs) was also decreased. EDMCs emerged as another major source of tumor-associated myeloid cells, further contributing to the suppressive TiME. These results provide a novel model of hematopoietic diversion in which myeloma “hijacks” CD45⁺ erythroid progenitor cells, redirecting them toward a myeloid fate to evade immune surveillance. EDMCs, as potent immunosuppressive players, strongly inhibit CD8⁺ T cell function and accelerate disease progression. Additionally, our findings establish a mechanistic link between LILRB4 and MM-associated anemia, a well-known poor prognostic factor.Our study therefore suggests that LILRB4 overexpression induces key molecular changes that enable macrophage inflammatory protein-1 alpha (MIP-1α/CCL3)-mediated formation of an immunosuppressive myeloid tumor microenvironment, thereby promoting MM cell growth and survival.