Tumor immune microenvironmental alterations occur early in multiple myeloma (MM) development. In this study, we aim to systematically characterize the tumor immune microenvironment (TME) and the tumor-immune interactions from precursor stages, i.e., monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM), to newly diagnosed MM, comparing these to healthy donors. Using CIBERSORT, mass cytometry (CyTOF), and single-cell RNA sequencing (scRNA-Seq), we examined innate and adaptive immune changes across these stages. We found a decrease in granulocytes in the TME predicts MM outcomes. HLA-DR is reduced in CD16⁺ monocytes and plasmacytoid dendritic cells, while myeloid dendritic cells show decreased expression of stress and immune-response genes. NK cells and CD8⁺ T cells shift from a GZMK⁺ to a GZMB⁺ cytotoxic phenotype in the TME, with increased inhibitory markers TIM3 and TIGIT. In paired samples, the proportion and gene expression pattern in patient-specific GZMB⁺CD8⁺ T cells remain largely unchanged despite MM progression. Our findings provide a comprehensive immune landscape of MM and its precursors, offering insights into therapeutic strategies. Enhancing neutrophil and NK cell cytotoxicity, tumor antigen presentation, and CD8⁺ T cell versatility in precursor stages may prevent MM progression.

肿瘤免疫微环境改变发生在多发性骨髓瘤 （MM） 发展的早期。在这项研究中，我们旨在系统地表征肿瘤免疫微环境 （TME） 和从前体阶段（即意义未明的单克隆丙种球蛋白病 （MGUS） 和阴燃性 MM （SMM））到新诊断的 MM，将它们与健康供体进行比较。使用 CIBERSORT、质谱流式细胞术 （CyTOF） 和单细胞 RNA 测序 （scRNA-Seq），我们检查了这些阶段的先天性和适应性免疫变化。我们发现 TME 中粒细胞的减少可预测 MM 结局。CD16⁺ 单核细胞和浆细胞样树突状细胞中的 HLA-DR 降低，而髓样树突状细胞显示应激和免疫反应基因的表达降低。NK 细胞和 CD8⁺ T 细胞在 TME 中从 GZMK⁺ 转变为 GZMB⁺ 细胞毒性表型，抑制标志物 TIM3 和 TIGIT 增加。在配对样本中，尽管 MM 进展，但患者特异性 GZMB⁺CD8⁺ T 细胞中的比例和基因表达模式基本保持不变。我们的研究结果提供了 MM 及其前体的全面免疫景观，为治疗策略提供了见解。在前体阶段增强中性粒细胞和 NK 细胞的细胞毒性、肿瘤抗原呈递和 CD8⁺ T 细胞的多功能性可以预防 MM 进展。