IL-6-driven metabolic reprogramming of the multiple myeloma microenvironment

Abstract

Multiple myeloma is an aggressive plasma cell malignancy that remains incurable despite major therapeutic advances and depends on extensive metabolic remodeling to support malignant growth and drug resistance. Although tumor cell-intrinsic mechanisms of drug resistance are well characterized, the contribution of cells in the tumor microenvironment, particularly bone marrow stromal cells, to metabolic remodeling and therapeutic resistance remains poorly understood. We combined [U- 13 C]glucose tracing metabolomics with a metabolomics-compatible co-culture system of multiple myeloma and bone marrow stromal cells to assess the impact of co-culture on metabolic pathway activity across genetically distinct multiple myeloma cell lines. Cells were additionally subjected to cytokine analysis, gene expression analysis and drug response assays to investigate associations between metabolic changes, treatment responses and cytokine abundances. Bone marrow stromal cell co-culture induced a convergent metabolic rewiring in multiple myeloma cells, enhancing pathways previously linked to bortezomib resistance, including glycolysis, tricarboxylic acid cycle activity, serine synthesis and nucleotide biosynthesis. In parallel, stromal cells acquired a cancer-associated fibroblast-like phenotype characterized by increased interleukin-6 and transforming growth factor-β production. This cytokine milieu promoted bortezomib resistance and stromal cell activation. Interleukin-6 alone was sufficient to rescue multiple myeloma cells from bortezomib-induced cytotoxicity and reproduced a substantial fraction of the co-culture-induced metabolic remodeling. Analysis of patient proteomics revealed a strong positive association between interleukin-6 abundance and expression of enzymes involved in mitochondrial metabolism, glycolysis, serine metabolism, nucleotide metabolism and redox homeostasis. These findings identify bone marrow stromal cell-derived interleukin-6 as a central driver of tumor microenvironment-mediated metabolic reprogramming and bortezomib resistance in multiple myeloma. Targeting interleukin-6-dependent metabolic signaling may represent a promising strategy to overcome stromal-driven therapeutic resistance. Not applicable.