NAMPT in macrophages promotes multiple myeloma drug resistance through mitochondrial metabolic reprogramming and modulates immunosuppression via the SIRT1/STAT3/SPP1 axis.

作者：Shunnan Yao, Gang Xiao, Xi Huang, Qi-Qi Shen, Haoguang Chen, Chunting Zhu, Shengchun Jin, Enfan Zhang, Zhen Cai · 发表于：Blood · 年份：2025 · DOI：10.1182/blood-2025-5707 · 被引用次数：1 · 研究领域：Sirtuins and Resveratrol in Medicine、Biochemical and Molecular Research、PARP inhibition in cancer therapy

Abstract Introduction: Macrophages (MΦs) are key components of the multiple myeloma (MM) tumor microenvironment (TME) and contribute to drug resistance, but the mechanisms underlying their crosstalk with MM cells and other immune cells are yet to be elucidated. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme responsible for NAD+ biosynthesis, has been reported to promote tumorigenesis, drug resistance and immunosuppression. Previously, we identified a subgroup of MΦs with high expression of NAMPT through single-cell RNA sequencing (scRNA-seq) of MM bone marrow. Consequently, unraveling the regulation of NAMPT in MΦs is essential for developing potent therapeutic strategies against MM. Methods: To characterize macrophage subpopulations, we performed scRNA-seq of MM bone marrow samples obtained from newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM) patients. PBMC were incubated for 7 days in medium with M-CSF to become normal MΦs. MΦs were cultured for 72 hours with myeloma-conditioning medium to generate myloma-associated MΦs (mMΦs). We suppressed NAMPT in MΦs through siRNA-mediated knockdown (KD) and FK866 inhibition. Then functional rescue was achieved by supplementing downstream metabolite NMN. Using co-culture models, we assessed the impact of mMΦs on the drug resistance of MM and regulation of CD8+T cells cytotoxic activity, as well as the downstream signaling mechanism through in vitro and in vivo experiments. Results: We found that NAM...