This study reveals a novel mechanism by which monocytes in the bone marrow microenvironment transfer functional mitochondria to multiple myeloma cells via the CD38-CD31 axis, thereby driving oxidative phosphorylation metabolic reprogramming and inducing drug resistance. These findings provide direct experimental evidence for combination therapeutic strategies targeting the tumor metabolic microenvironment.
Literature Overview
The article titled 'Monocyte‐mediated metabolic rewiring via CD31‐CD38 interactions promotes growth and drug‐resistance in multiple myeloma,' published in the journal HemaSphere, systematically investigates how monocytes in the bone marrow microenvironment reprogram the metabolic phenotype of multiple myeloma (MM) cells through mitochondrial transfer, thereby promoting tumor growth and drug resistance. The study focuses on the CD38-CD31 interaction mechanism and reveals the dual regulatory role of the clinical drug daratumumab: while it blocks mitochondrial donation from monocytes, it simultaneously induces monocytes to 'steal' mitochondria from tumor cells via trogocytosis. This finding expands our understanding of microenvironment-mediated drug resistance.Background Knowledge
Multiple myeloma (MM) is a malignant plasma cell disorder that depends on the bone marrow microenvironment for survival. Although treatment has advanced, drug resistance remains a major clinical challenge. Stromal and immune cells in the bone marrow support MM cell survival through direct contact or secreted factors. Recent studies have shown that tumor cells can acquire 'mitochondrial transfer' from neighboring cells to gain energy production capacity, enhancing their metabolic adaptability. However, which microenvironmental cells participate in this process, the underlying molecular mechanisms, and their impact on treatment response remain unclear. CD38, a surface antigen highly expressed on MM cells, is not only a therapeutic target but also involved in intercellular communication. This study proposes the hypothesis that 'monocytes may transfer mitochondria to MM cells via CD31-CD38 interactions,' based on the potential non-immunological functions of CD38 in cell-cell contact, addressing a key bottleneck in microenvironmental metabolic support research and offering a new perspective on daratumumab resistance mechanisms.
Research Methods and Experiments
The authors employed multiple experimental systems to validate the mitochondrial transfer mechanism. First, monocytes from healthy donors were co-cultured with bone marrow mononuclear cells (BM-MNCs) from newly diagnosed MM patients using a transwell system. By labeling monocyte mitochondria with MitoTracker Deep Red, they observed mitochondrial transfer to CD138+ MM cells. Using a 3.0 μm pore size system, they confirmed that this transfer does not depend on direct nanotube connections. Furthermore, co-culturing the THP-1 monocyte cell line with MM cell lines of different CD38 expression status (e.g., UM9, U266) revealed that only CD38+ cells received mitochondria, a process blocked by daratumumab or anti-CD31 antibodies, indicating that CD38-CD31 interaction is the key molecular axis. The authors also isolated mitochondrial-enriched extracellular vesicles (Mt-EVs) from monocytes, demonstrating that these vesicles express CD31 on their surface and can deliver functional mitochondria to MM cells in a CD38-dependent manner, enhancing oxidative phosphorylation (OXPHOS).
To investigate clinical relevance, the study used BM-MNCs from both newly diagnosed and daratumumab-resistant patients to evaluate the impact of Mt-EVs on drug sensitivity. Seahorse analysis confirmed that Mt-EVs significantly increased the OCR (oxygen consumption rate) of MM cells without significantly affecting ECAR (glycolysis), indicating a metabolic shift toward OXPHOS. Functionally, Mt-EVs promoted MM cell proliferation and migration and induced resistance to bortezomib and doxorubicin, but did not affect sensitivity to pomalidomide. Notably, in the presence of daratumumab, monocytes instead acquired mitochondria from MM cells via Fc receptor-mediated trogocytosis, leading to reduced mitochondrial content in MM cells and thus enhanced drug sensitivity. This phenomenon did not occur in UM9-CD38KO cells, confirming its CD38 dependence.Key Conclusions and Perspectives
Research Significance and Prospects
This study profoundly changes our understanding of metabolic interactions within the bone marrow microenvironment. Previously, the microenvironment was thought to only provide survival signals, but this work reveals it can directly 'donate' energy organelles, granting tumor cells greater metabolic plasticity. This finding has important implications for drug development: anti-CD38 antibodies may not only act through immune mechanisms such as ADCC but also enhance chemosensitivity by blocking metabolic support. Therefore, future efforts should explore combining metabolic inhibitors with anti-CD38 antibodies to overcome microenvironment-mediated resistance.
In terms of clinical monitoring, the proportion of monocytes or levels of Mt-EVs in patient bone marrow may serve as predictive biomarkers for drug resistance. Additionally, the study suggests that daratumumab resistance may be linked to monocyte functional exhaustion or reduced CD31 expression, warranting validation in longitudinal samples. For disease modeling, current MM animal models often inadequately reconstruct the human bone marrow microenvironment. Future models should incorporate humanized immune systems with monocytes/macrophages to more accurately simulate mitochondrial transfer and improve the clinical predictive value of drug efficacy evaluations.
Conclusion
This study systematically reveals a novel mechanism by which monocytes transfer mitochondria to multiple myeloma cells via the CD31-CD38 axis, driving a metabolic shift toward OXPHOS and thereby promoting tumor growth and drug resistance. This discovery not only expands our understanding of the supportive functions of the bone marrow microenvironment but also redefines the mode of action of daratumumab—positioning it not merely as a targeted therapy but as a 'regulator' of microenvironmental metabolic reprogramming. From bench to bedside, this work provides a solid theoretical foundation for developing combination therapies targeting the tumor’s metabolic microenvironment. For example, clinical trials could be designed to evaluate the efficacy of combining anti-CD38 antibodies with OXPHOS inhibitors (e.g., IACS-010759). Furthermore, measuring the frequency of mitochondrial exchange between monocytes and MM cells in patient bone marrow may serve as a biomarker for personalized therapy. Overall, this study identifies a critical node in the precision treatment of multiple myeloma and represents a significant milestone bridging basic discovery and clinical translation.
