Bone marrow stromal cells drive IL-6 metabolic rewiring and bortezomib resistance in multiple myeloma

Multiple myeloma remains an aggressive and incurable plasma cell malignancy despite major therapeutic advances, and new research now points to the bone marrow microenvironment itself as a key accomplice in the disease’s resistance to treatment. A study published in Cancer & Metabolism on 6 August 2026 reports that bone marrow stromal cells reprogram the metabolism of myeloma cells through interleukin-6 signaling, weakening the effectiveness of the widely used proteasome inhibitor bortezomib.

The research team, led by María Matamala Montoya, Silke Eleveld, Esther A. Zaal and Celia R. Berkers, combined [U-13C]glucose tracing metabolomics with a metabolomics-compatible co-culture system of multiple myeloma and bone marrow stromal cells. This approach allowed them to assess how co-culture altered metabolic pathway activity across genetically distinct myeloma cell lines. The cells were also subjected to cytokine analysis, gene expression analysis and drug response assays to investigate associations between metabolic changes, treatment responses and cytokine abundances.

The results showed that bone marrow stromal cell co-culture induced a convergent metabolic rewiring in multiple myeloma cells, enhancing pathways previously linked to bortezomib resistance. These included glycolysis, tricarboxylic acid cycle activity, serine synthesis and nucleotide biosynthesis. In parallel, the stromal cells themselves acquired a cancer-associated fibroblast-like phenotype characterized by increased production of interleukin-6 and transforming growth factor-β.

According to the study, this cytokine milieu promoted bortezomib resistance and stromal cell activation. Remarkably, interleukin-6 alone was sufficient to rescue multiple myeloma cells from bortezomib-induced cytotoxicity and reproduced a substantial fraction of the metabolic remodeling observed in the full co-culture system, identifying this single signaling molecule as a central mediator of the stromal effect.

The findings were not limited to laboratory models. Analysis of patient proteomics revealed a strong positive association between interleukin-6 abundance and the expression of enzymes involved in mitochondrial metabolism, glycolysis, serine metabolism, nucleotide metabolism and redox homeostasis, supporting the relevance of the co-culture findings to the human disease setting.

While tumor cell-intrinsic mechanisms of drug resistance are well characterized, the authors note in their background that the contribution of cells in the tumor microenvironment, particularly bone marrow stromal cells, to metabolic remodeling and therapeutic resistance remains poorly understood.

The study’s conclusions identify bone marrow stromal cell-derived interleukin-6 as a central driver of tumor microenvironment-mediated metabolic reprogramming and bortezomib resistance in multiple myeloma. The authors suggest that targeting interleukin-6-dependent metabolic signaling may represent a promising strategy to overcome stromal-driven therapeutic resistance, though this remains a proposed direction rather than a demonstrated clinical outcome.

Because the work relies on cell line co-culture models and patient proteomic associations, the results describe mechanistic links and correlations rather than confirmed clinical efficacy. The article was published as an open-access research paper and, at the time of this report, is being shared early as a peer-reviewed, accepted version of record that is citable and carries a permanent DOI, subject to further edits.

Subject of Research: Interleukin-6-driven metabolic reprogramming of the multiple myeloma microenvironment and its role in bortezomib resistance

Article Title: IL-6-driven metabolic reprogramming of the multiple myeloma microenvironment

Article References: Matamala Montoya, M., Eleveld, S., Zaal, E. A., & Berkers, C. R. (2026). IL-6-driven metabolic reprogramming of the multiple myeloma microenvironment. Cancer & Metabolism. https://doi.org/10.1186/s40170-026-00451-4

Image Credits: AI Generated

DOI: 10.1186/s40170-026-00451-4

Keywords: multiple myeloma, bone marrow stromal cells, interleukin-6, bortezomib resistance, metabolic reprogramming, glycolysis, TCA cycle, serine synthesis, nucleotide biosynthesis, tumor microenvironment, cancer-associated fibroblasts, metabolomics