Single-cell RNA sequencing reveals immune regulatory mechanisms and molecular therapeutic strategies in the microenvironment of multiple myeloma - Research study

Sep 23, 2026

Multiple myeloma remains incurable due to relapse and drug resistance, driven by complex interactions within the myeloma microenvironment. The study uses single-cell RNA sequencing to dissect tumor, immune, and stromal cell crosstalk, supported by pathway analysis and Mendelian randomization to infer causal immune–gene relationships. Cell–cell communication mapping highlights key ligand–receptor axes, while molecular docking screens small-molecule candidates targeting immune-associated proteins, proposing immune modulation and specific targets as therapeutic strategies.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages19

Reading Time48 min

AccessFree to download

Background

Methods

Results

Conclusions

Introduction

Single-cell RNA sequencing reveals immune regulatory mechanisms and molecular therapeutic strategies in the microenvironment of multiple myeloma Qiang Su, MDa , Kehan Long, MDb , MoZiLi Adu, PhDc , Meijun Jiang, MDd , Qiaochu Li, PhDe , Xufeng Wan, PhDa , Jian Cao, MDa , Yan Yue, PhDa , Shuoyuan Li, MDa , Zhendong Ying, MDf , Qibin Liu, MDg , Chaoqun You, PhDh ,*, Zhuang Zhang, PhDa ,*, Duan Wang, PhDa ,* Background: Multiple myeloma (MM) is a malignancy marked by uncontrolled plasma cell proliferation, immune evasion, and drug resistance. Despite advances in treatment, the disease remains incurable due to relapses and drug resistance. This study aims to investigate the molecular and cellular interactions within the myeloma microenvironment using single-cell RNA sequencing (scRNA-seq), Mendelian randomization (MR), and pathway analysis to uncover therapeutic targets. Methods: We used scRNA-seq to analyze tumor, immune, and stromal cell interactions in MM. Data were processed using Seurat for clustering, dimensionality reduction, and cell-type annotation. Gene Set Variation Analysis (GSVA) and cell–cell interaction analysis were performed to identify signaling pathways involved in disease progression. Two-sample MR was applied to explore causal relationships between genetic variants and gene expression. Finally, molecular docking simulations were used to identify potential small molecule modulators of key proteins involved in MM. Results: We identified significant immune-related signaling pathways, including PI3K-AKT-mTOR, WNT-β-catenin, and TGF-β , upregulated in immune cells within the MM microenvironment. Genes such as HLA-C, CTSS, and LRRFIP1 showed positive causal relationships with MM, while SHISA5 and ISG15 exhibited protective roles. Cell communication analysis revealed key ligand– receptor interactions between immune and tumor cells. Molecular docking identified promising small molecules like actein andaflatoxin B1 targeting ISG15 and TAGLN2 . Conclusions: This study reveals key genetic drivers and immune modulation mechanisms in MM. Targeting immune-related pathways, such as PI3K-AKT-mTOR and WNT-β-catenin, and small molecules targeting ISG15 and TAGLN2 could offer new therapeutic strategies. Keywords: immune modulation, Mendelian randomization, molecular docking, multiple myeloma, scRNA-seq, therapeutic targets Introduction Multiple myeloma (MM) is a serious blood cancer in which plasma cells begin to proliferate uncontrollably in the bone marrow, leading to severe health complications and, unfortunately, high mortality rates[1,2] . Clinically, the disease is marked by the presence of abnormal monoclonal proteins, or M-proteins, in the blood or urine[3] . Alongside this, patients often face a range of debilitating issues like anemia, bone damage, kidney failure, anda weakened immune system [4] . Even though modern treatments – such as proteasome inhibitors, immunomodulatory aOrthopedic Research Institute and Department of Orthopedics, West China Hospital, Sichuan University, Chengdu 610041, China, bSchool of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, China, cResearch Center for Traditional Chinese Medicine Resources and Ethnic Minority Medicine, Jiangxi University of Chinese Medicine, Nanchang, China, dDepartment of Hand and Podiatric Surgery, Orthopedics Center, The First Hospital of Jilin University, Changchun, People’s Republic of China, eDepartment of Orthopedics, the First Affiliated Hospital, Chongqing Medical University, Chongqing, China, fDepartment of Orthopedics, School of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Shandong Qianfoshan Hospital, Jinan, China, gAffiliated Hospital of Shandong Second Medical University, Jinan, China and hMusculoskeletal Tumor Center, Beijing Key Laboratory of Musculoskeletal Tumor, Peking University People’s Hospital, Beijing, China Qiang Su, Kehan Long, and MoZiLi-Adu have contributed equally to

FAQs

What problem does the study address in multiple myeloma?

It addresses why multiple myeloma remains incurable, focusing on relapse, drug resistance, and immune evasion driven by interactions in the myeloma microenvironment.

Which analytical approaches are used to uncover therapeutic targets?

The study combines single-cell RNA sequencing with clustering and pathway analysis, Mendelian randomization for causal inference, cell–cell interaction analysis, and molecular docking for small-molecule candidate identification.

What immune-related pathways are highlighted in the results?

Significant immune-related signaling pathways upregulated in immune cells include PI3K-AKT-mTOR, WNT-β-catenin, and TGF-β.

How do the study findings suggest new molecular therapeutic strategies?

They propose targeting immune-related pathways and small molecules predicted to modulate key proteins, including candidates linked to ISG15 and TAGLN2.

Sep 23, 2026

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