Your new experience awaits. Try the new design now and help us make it even better

ORIGINAL RESEARCH article

Front. Immunol.

Sec. Cancer Immunity and Immunotherapy

Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1653096

This article is part of the Research TopicTumor Microenvironment: Inflammation and Immune Signal Transduction at Single-Cell ResolutionView all 8 articles

Single-Cell Profiling Delineates the Tumor Microenvironment and Immunological Networks in Patient-Derived Uterine Leiomyosarcoma

Provisionally accepted
Yi  GuoYi Guo1Dongsheng  ShenDongsheng Shen2YUHANG  XIAOYUHANG XIAO1Chenghao  WuChenghao Wu3Meiyi  ChenMeiyi Chen2Lina  YangLina Yang4Huaifang  LiHuaifang Li2Xiaowen  TongXiaowen Tong2Rujun  ChenRujun Chen5*Fang  LiFang Li1*
  • 1Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
  • 2Tongji Hospital Affiliated to Tongji University, Shanghai, China
  • 3Shanghai Jiao Tong University School of Medicine Affiliated International Peace Maternal and Child Health Hospital, Shanghai, China
  • 4Fudan University Shanghai Cancer Center, Shanghai, China
  • 5Fifth People's Hospital of Shanghai Fudan University, Shanghai, China

The final, formatted version of the article will be published soon.

Background: Uterine leiomyosarcoma (ULSA) is a highly aggressive gynecologic malignancy characterized by early metastasis, profound immunosuppression, and resistance to conventional therapies, including immune checkpoint blockade (ICB). The intricate tumor microenvironment (TME) and cellular heterogeneity driving its progression and therapy resistance remain poorly defined.We performed single-cell RNA sequencing (scRNA-seq) on metastatic lesions (pelvic cavity, rectum, peritoneum, bladder) from a treatment-naïve ULSA patient and compared them to normal uterine myometrium (n=5). Integrated analyses included cellular composition mapping, copy number variation (CNV) assessment, pseudotemporal trajectory reconstruction, cell-cell communication inference, functional enrichment, and validation via multiplex immunofluorescence (mpIF).Survival correlations were assessed using the TCGA-SARC cohort.Results: In this study, the main finding is that the tumor microenvironment (TME) has a strong immunosuppressive effect. Firstly, its characteristic is exhausted CD8 + T cells. This study found that as time progresses, the initial cell markers (CCR7, MAL) gradually disappear, while the exhaustion markers (LAG3, HAVCR2, TIGIT) are enriched. This is associated with poor prognosis. Secondly, the M2-polarized macrophages are mainly composed of M2-like tumor-associated macrophages (TAMs) with tumor-promoting characteristics (CD163, FTH1, FTL, TIMP1), and there is a polarization from M1 to M2. Finally, the immature, tumor-promoting N2 neutrophils (CD15 + EDARADD + ) enriched in the metastatic foci are associated with poor prognosis.The cell communication involves the interaction of MIF/CD74 + CD44 between T/B cells, as well as the role of the CXCL8 signaling axis in promoting angiogenesis, TAM polarization, and immunosuppression.For the first time, a comprehensive single-cell map of ULSA was constructed, depicting a metastasis-susceptible cell subset (U11-EDARADD) and an extremely immunosuppressed tumor microenvironment dominated by depleted CD8 + T cells, M2 macrophages and N2 neutrophils. These features shed light on the underlying mechanisms of chemotherapy resistance and immunotherapy failure. The biomarkers identified here (EDARADD, CLDN10, TMIGD2) as well as the dysregulated pathways (TGF-β, angiogenesis, MIF signaling) provide possible targets for future development of combined immunotherapy strategies against this deadly disease.

Keywords: Uterine leiomyosarcoma, metastasis, Tumor microenvironments, single-cell RNA sequencing, prognosis, T cell, macrophage

Received: 24 Jun 2025; Accepted: 06 Aug 2025.

Copyright: © 2025 Guo, Shen, XIAO, Wu, Chen, Yang, Li, Tong, Chen and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Rujun Chen, Fifth People's Hospital of Shanghai Fudan University, Shanghai, China
Fang Li, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.