Adrenergic stimulation of bone marrow immunity differentially affects myeloma growth and immunotherapy responses

Adrenergic signaling regulates immune homeostasis through neuroendocrine pathways, but its role in hematologic malignancies remains poorly understood. Multiple myeloma (MM) originates in the bone marrow (BM), a highly innervated niche where neural, immune, and stromal signals are integrated. Whether adrenergic stimulation shapes BM immunity and influences myeloma progression is unclear. Using the 5T33MM mouse model, we investigated how adrenergic activation affects tumor growth and the BM immune landscape. Sustained adrenergic signaling was induced in vivo, while pharmacological β-adrenergic stimulation was used to assess effects on tumor-immune interactions. Immune composition and tumor burden were analyzed in BM and spleen, β₂-adrenergic receptor expression was examined across murine and human immune populations, and ex vivo assays were performed using murine and patient-derived BM samples treated with adrenergic agonists alone or combined with relevant myeloma immunotherapies. Chronic restraint stress remodeled the BM immune compartment in MM-bearing mice, characterized by expansion of innate effector populations, including neutrophils and natural killer cells, and was associated with a significant reduction in BM tumor burden. These effects were compartment-restricted and not reflected in splenic tumor load or systemic disease markers. Pharmacological β-adrenergic stimulation reproduced these immune alterations and transiently delayed myeloma progression. In contrast, short-term β-adrenergic agonism ex vivo did not alter MM cell viability but consistently reduced the efficacy of MM immunotherapies. In summary, adrenergic signaling exerts context-dependent effects on myeloma progression, restraining tumor growth in vivo while impairing immunotherapy efficacy ex vivo, identifying a BM-specific neuroimmune axis relevant for cancer treatment.