肿瘤微环境（TME）在多发性骨髓瘤（MM）的疾病进展中发挥了关键作用。本研究旨在呈现MM-TME在疾病进展中的图谱，并探索TME导向的治疗策略。我们对来自不同疾病阶段的样本进行了单细胞RNA测序（scRNAseq）。我们通过批量RNAseq、流式细胞术（FCM）、体外和体内功能实验验证了这些发现。我们描述了在疾病进展过程中存在的一种受损TME，其特征为耗竭性NK细胞和CD8 + T细胞富集，并改编巨噬细胞（MPs）。重新编程的肿瘤相关MP（TAMs）显示出混合表型，同时具有M1和M2特征。其中有两个TAM簇专门出现在MM阶段，显示更高的M2得分。我们在临床队列中验证了TAM中混合的M1 / M2表型，并验证了重新编程的TAM的吞噬功能障碍。细胞相互作用分析确定了MP和恶性浆细胞（PCs）之间两个富集的配体-受体对，包括抑制吞噬作用的SIRPA-CD47通路和重塑MP表型的CD74-MIF（巨噬细胞抑制因子）。CD47和MIF的表达与疾病进展和不良结局相关。我们设计了一种双重MP靶向策略，将抗CD47抗体和MIF抑制剂结合起来，以激活吞噬作用并重构MP到功能表型，并证明了其在体外和体内具有强大的抗肿瘤效果。我们总结了MM-TME在疾病进展期间的变化并解决了TAM的重编程问题。双重MP靶向方法阻断了CD47和MIF，显示出强大的抗肿瘤效果。 ©2023英国血液学会和John Wiley＆Sons Ltd。

The tumour microenvironment (TME) plays a critical role in disease progression in multiple myeloma (MM). This study aimed to present an atlas of MM-TME in disease progression and explore TME-directed therapeutic strategies. We performed single-cell RNA sequencing (scRNAseq) in samples from different disease stages. We validated the findings by bulk RNAseq, flow cytometry (FCM) and in vitro and in vivo functional experiments. We delineated a compromised TME during disease progression, characterized by enrichment of exhausted NK cells and CD8+ T cells and reprogramming of macrophages (MPs). The reprogrammed tumour-associated MPs (TAMs) displayed a mixed phenotype showing both M1 and M2 features, with two TAM clusters exclusively present in the MM stage showing higher M2 scores. We validated the mixed M1/M2 phenotype in TAMs in a clinical cohort and verified phagocytic dysfunction in reprogrammed TAMs. Cellular interaction analysis identified two enriched ligand-receptor pairs between MPs and malignant plasma cells (PCs), including the SIRPA-CD47 pathway suppressing phagocytosis and the CD74-MIF (macrophage inhibitory factor) reshaping the phenotype of MPs. The expression of CD47 and MIF correlated with disease progression and adverse outcomes. We designed a dual-MP-targeted strategy by combining an anti-CD47 antibody and MIF inhibitor to activate phagocytosis and repolarize MP to a functional phenotype and proved its potent antitumour effect in vitro and in vivo. We drafted alterations in MM-TME during disease progression and unravelled TAM's reprogramming. The dual MP-targeted approach blocking both CD47 and MIF showed potent antitumour effects.© 2023 British Society for Haematology and John Wiley & Sons Ltd.