{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T05:55:23Z","timestamp":1776318923937,"version":"3.50.1"},"reference-count":62,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T00:00:00Z","timestamp":1776297600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1760136","type":"journal-article","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T05:25:19Z","timestamp":1776317119000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Macrophage and IL-6 signaling modulate multiple myeloma progression and response to metformin and CAR-T cell therapy"],"prefix":"10.3389","volume":"17","author":[{"given":"Xuanyou","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine, Mayo Clinic","place":["Rochester, MN, United 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