Background: Multiple myeloma (MM) is a hematologic malignancy characterized by the clonal proliferation of plasma cells, with extramedullary myeloma (EMM) being an aggressive form involving malignant infiltration beyond the bone marrow. Copper metabolism is essential for tumor proliferation and metastasis, with copper metabolism MURR1 domain (COMMD) proteins regulating these processes and maintaining copper homeostasis. Dysregulated copper homeostasis contributes to cancer progression, including MM, with elevated copper levels linked to disease aggressiveness and poor prognosis. This study investigates the role of the COMMD3 in mediating MM cell progression, particularly its influence on copper metabolism. Methods: Comprehensive bioinformatics analyses were conducted on bone marrow and extramedullary samples to determine the expression of COMMD3, which was validated through in vitro and in vivo functional assays. The MM cell lines RPMI8226 and MM1S underwent lentiviral transfection for COMMD3 overexpression and knockdown. RNA sequencing was conducted on COMMD3 knockdown cells to identify differentially expressed genes. Functional assays measured cell proliferation, migration, apoptosis, and copper metabolism, with a non-obese diabetic severe combined immune-deficiency gamma (NSG) mouse xenograft model providing in vivo validation. Results: Elevated COMMD3 expression was correlated with extramedullary myeloma and poor prognosis in MM patients. COMMD3 promoted MM cell proliferation and migration, modulating intracellular copper levels, likely through the ATOX1-ATP7A-LOX copper-metabolism-related pathway. High ATOX1 expression was correlated with worse outcomes, and ATOX1 inhibition abolished COMMD3’s effects. Conclusions: This study highlights the pivotal role of COMMD3 in MM progression, particularly via the ATOX1-ATP7A-LOX axis. These findings provide insights into EMM mechanisms and position COMMD3 as a potential therapeutic target. Future research is needed to validate these findings in larger clinical cohorts and to unravel the precise molecular interactions between COMMD3 and copper metabolism proteins.

Hematologic malignancies (HMs), which originate from hematopoietic or lymphoid tissues, pose a significant therapeutic challenge due to issues such as drug resistance, relapse, and treatment-related toxicity. The tumor microenvironment (TME), especially within the bone marrow niche, is now widely recognized as a critical determinant of disease progression and treatment response. A central mechanism within this specialized niche is the extensive metabolic reprogramming of key stromal and immune cells, including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts (CAFs), and bone marrow adipocytes (BMAds). This review systematically elaborates on the alterations in glucose, lipid, and amino acid metabolism within these cellular compartments of the HM-TME. We detail how metabolites such as lactate, fatty acids, and itaconate function not merely as metabolic byproducts but as active signaling molecules that drive critical processes like immune cell polarization, stromal remodeling, and intricate metabolic crosstalk. This comprehensive reprogramming collectively fosters a profoundly immunosuppressive milieu, promotes tumor cell survival and proliferation, and confers resistance to conventional and novel therapies. Furthermore, we explore emerging therapeutic strategies designed to target these metabolic vulnerabilities. These include inhibitors of specific metabolic pathways, modulators of metabolite-driven signaling, and innovative approaches such as nanomedicine and metabolically enhanced immunotherapy. Finally, we outline the current challenges in the field—such as intra-tumoral metabolic heterogeneity and the pressing need for targeted delivery systems—and discuss future perspectives involving advanced technologies like single-cell metabolomics and rational combination strategies. In summary, this synthesis aims to provide a comprehensive and rational foundation for developing novel immunometabolic interventions against HMs, highlighting the therapeutic potential of disrupting the metabolic dialogue within the TME.