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Research Article: Macrophage and IL-6 signaling modulate multiple myeloma progression and response to metformin and CAR-T cell therapy

Date Published: 2026-04-16

Abstract:
The tumor microenvironment (TME) plays a crucial role in tumor progression and therapeutic response. Monocytes and macrophages, depending on their phenotype, can either enhance anti-tumor immunity or promote tumor growth by regulating cytokines such as IL-6. Multiple myeloma (MM), a hematologic malignancy, expresses the IL-6 receptor CD126 on its surface. Chimeric antigen receptor (CAR)-T cells targeting CD126 have been developed and shown to effectively eliminate CD126-positive tumor cells. However, interactions between macrophages, myeloma cells, and CAR-T cells require further investigation to optimize treatment strategies and minimize adverse effects. In this study, THP-1-derived macrophages, CD126 CAR-T cells, and MM cells, especially RPMI 8226 cells, were used to explore these interactions. A reduced cell population and an increased apoptosis of RPMI 8226 cells were observed in the presence of M1 macrophages. Metformin, known to influence IL-6 production, reduced the viability of RPMI 8226 cells with decreased CD126 expression. However, the killing activity of CD126 CAR-T cells against RPMI 8226 cells decreased after co-culture with macrophages, likely due to interactions between the CAR-T cells and the macrophages. These findings highlight the significant role of macrophages and inflammatory responses in MM progression and in modulating the efficacy of CAR-T cell therapy, providing valuable insights for the optimization of immunotherapeutic strategies.

Introduction:
Multiple myeloma (MM) is a hematologic malignancy marked by the abnormal growth of plasma cells. Despite advancements in treatment, MM remains an incurable disease due to its complex biology and interactions within the tumor microenvironment (TME) ( 1 ). The TME, consisting of various immune cells, stromal cells, cytokines, and extracellular matrix components, plays a critical role in disease progression, immune evasion, and resistance to therapy ( 2 ). In the TME, macrophages are highly plastic and can adopt…

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