多发性骨髓瘤（MM）仍然是一种无法治愈的血液恶性肿瘤。尽管治疗取得了巨大进步，但约 10% 的患者预后仍然很差，中位总生存期不到 24 个月。我们的研究旨在强调与疾病快速进展相关的关键机制，并为这些超高危患者提供新的治疗选择。我们利用单细胞转录组测序来剖析生存少于两年的患者 (EM24) 的特征性骨髓生态位。值得注意的是，与持久缓解的患者相比，在 EM24 患者中观察到 LILRB4high 提前成熟浆细胞簇的富集。该簇表现出侵袭性增殖和耐药表型。高水平的 LILRB4 促进 MM 克隆形成和进展。临床上，LILRB4的高表达与新诊断的MM患者和复发/难治性MM患者的不良预后相关。 ATAC-seq 分析发现，高染色体可及性导致 MM 细胞上 LILRB4 的升高。 CRISPR-Cas9删除LILRB4可减轻MM细胞的生长，抑制MDSC的免疫抑制功能，并进一步挽救MM微环境中的T细胞功能障碍。在 EM24 患者中也观察到更多的骨髓源性抑制细胞 (MDSC) 浸润。因此，我们创新性地产生了基于TCR的嵌合抗原受体（CAR）T细胞LILRB4-STAR-T。细胞毒性实验表明LILRB4-STAR-T细胞能有效消除肿瘤细胞并阻碍MDSCs功能。总之，我们的研究阐明 LILRB4 是高危 MM 的理想生物标志物和有前途的免疫治疗靶点。 LILRB4-STAR-T 细胞免疫疗法有望针对 MM 中的肿瘤细胞和免疫抑制肿瘤微环境。

Multiple myeloma (MM) remains an incurable hematological malignancy. Despite tremendous advances in the treatment, about 10% of patients still have very poor outcomes with median overall survival less than 24 months. Our study aimed to underscore the critical mechanisms pertaining to the rapid disease progression and provide novel therapeutic selection for these ultra-high-risk patients. We utilized single-cell transcriptomic sequencing to dissect the characteristic bone marrow niche of patients with survival of less than two years (EM24). Notably, an enrichment of LILRB4high pre-matured plasma-cell cluster was observed in the patients in EM24 compared to patients with durable remission. This cluster exhibited aggressive proliferation and drug-resistance phenotype. High-level LILRB4 promoted MM clonogenicity and progression. Clinically, high expression of LILRB4 was correlated with poor prognosis in both newly diagnosed MM patients and relapsed/refractory MM patients. The ATAC-seq analysis identified that high chromosomal accessibility caused the elevation of LILRB4 on MM cells. CRISPR-Cas9 deletion of LILRB4 alleviated the growth of MM cells, inhibited the immunosuppressive function of MDSCs, and further rescued T cell dysfunction in MM microenvironment. The more infiltration of myeloid-derived suppressive cells (MDSCs) was observed in EM24 patients as well. Therefore, we innovatively generated a TCR-based chimeric antigen receptor (CAR) T cell, LILRB4-STAR-T. Cytotoxicity experiment demonstrated that LILRB4-STAR-T cells efficaciously eliminated tumor cells and impeded MDSCs function. In conclusion, our study elucidates that LILRB4 is an ideal biomarker and promising immunotherapy target for high-risk MM. LILRB4-STAR-T cell immunotherapy is promising against tumor cells and immunosuppressive tumor microenvironment in MM.