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Peer-reviewedCC BY-NC-ND 4.0Cell Reports Medicine

Single-cell and spatial multi-omics reveal a recurrent multicellular niche at the tumor-stroma interface in multidrug resistance

  • Kangjie Shen1
  • Lu Wang2
  • Zixu Gao1
  • Junquan Song1
  • Qiangcheng Wang3
  • Minying Deng4
  • Yingcheng Wu5
  • Yang Yang1
  • Ming Ren6
  • Shengbai Xue7
  • Hongye Wang8
  • Wenyu Song9
14 more authors
  • Tianyi Zhang1
  • Chenlu Wei1
  • Jiangying Xuan1
  • Lilu Xie1
  • Yuan Gao1
  • Qianrong Hu1
  • Shaoluan Zheng1,10,11
  • Rongkui Luo4
  • Yingyong Hou4
  • Yuhong Zhou12
  • Fazhi Qi1
  • Jia Fan5
  • Chuanyuan Wei1
  • Jianying Gu1
12 affiliations
  1. 1Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
  2. 2Clinical Research Unit, Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai 200032, China
  3. 3Department of Radiation Oncology, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, Jiangsu 215001, China
  4. 4Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
  5. 5Department of Hepatobiliary Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai 200032, China
  6. 6Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
  7. 7Department of Oncology and State Key Laboratory of Systems Medicine for Cancer of Shanghai Cancer Institute, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
  8. 8Shanghai Cancer Institute, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
  9. 9Department of Cardiovascular Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
  10. 10Department of Plastic and Reconstructive Surgery, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, Fujian 361015, China
  11. 11Clinical Research Center for Precision Medicine of Abdominal Tumor of Fujian Province, Xiamen, Fujian 361015, China
  12. 12Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
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Abstract

Multi-drug resistance (MDR) is an almost inevitable endpoint of cancer therapy, driving rapid tumor progression, yet its evolutionary logic remains unclear because MDR tumors are rarely resected. Using paired therapy-naive and MDR melanoma specimens from a clinical trial, integrated with single-cell and spatial multi-omics and evaluated together with datasets from 10 additional cancer types, we identify a recurrent MDR-associated spatial nexus along the tumor-stroma interface. This niche juxtaposes CXCL14+ inflammatory cancer-associated fibroblasts (iCAFs), TREM2+ tumor-associated macrophages (TAMs), and AXL+ dedifferentiated tumor cells, and is accompanied by loss of tumor-reactive CXCL13+CD8+ T cells. In vitro, CXCL14 promotes macrophage migration and TREM2 induction, while TREM2+ TAMs suppress CXCL13+CD8+ T cells via CD86-CTLA4 signaling. TREM2+ TAMs also promote tumor dedifferentiation through oleic acid-driven GAS6-AXL activation. We develop an FAP/TREM2-targeting bispecific antibody to disrupt this spatial nexus and restore therapeutic sensitivity in MDR patient-derived xenograft models with favorable safety.

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Cite

BibTeXRIS
BibTeX
@article{shen2026singlecell,
  title = {{Single-cell and spatial multi-omics reveal a recurrent multicellular niche at the tumor-stroma interface in multidrug resistance}},
  author = {Kangjie Shen and Lu Wang and Zixu Gao and Junquan Song and Qiangcheng Wang and Minying Deng and Yingcheng Wu and Yang Yang and Ming Ren and Shengbai Xue and Hongye Wang and Wenyu Song and Tianyi Zhang and Chenlu Wei and Jiangying Xuan and Lilu Xie and Yuan Gao and Qianrong Hu and Shaoluan Zheng and Rongkui Luo and Yingyong Hou and Yuhong Zhou and Fazhi Qi and Jia Fan and Chuanyuan Wei and Jianying Gu},
  journal = {Cell Reports Medicine},
  year = {2026},
  month = sep,
  doi = {10.1016/j.xcrm.2026.103052},
  url = {https://doi.org/10.1016/j.xcrm.2026.103052},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Single-cell and spatial multi-omics reveal a recurrent multicellular niche at the tumor-stroma interface in multidrug resistance
AU  - Kangjie Shen
AU  - Lu Wang
AU  - Zixu Gao
AU  - Junquan Song
AU  - Qiangcheng Wang
AU  - Minying Deng
AU  - Yingcheng Wu
AU  - Yang Yang
AU  - Ming Ren
AU  - Shengbai Xue
AU  - Hongye Wang
AU  - Wenyu Song
AU  - Tianyi Zhang
AU  - Chenlu Wei
AU  - Jiangying Xuan
AU  - Lilu Xie
AU  - Yuan Gao
AU  - Qianrong Hu
AU  - Shaoluan Zheng
AU  - Rongkui Luo
AU  - Yingyong Hou
AU  - Yuhong Zhou
AU  - Fazhi Qi
AU  - Jia Fan
AU  - Chuanyuan Wei
AU  - Jianying Gu
PY  - 2026
DA  - 2026/09/16
JO  - Cell Reports Medicine
DO  - 10.1016/j.xcrm.2026.103052
UR  - https://doi.org/10.1016/j.xcrm.2026.103052
AB  - Multi-drug resistance (MDR) is an almost inevitable endpoint of cancer therapy, driving rapid tumor progression, yet its evolutionary logic remains unclear because MDR tumors are rarely resected. Using paired therapy-naive and MDR melanoma specimens from a clinical trial, integrated with single-cell and spatial multi-omics and evaluated together with datasets from 10 additional cancer types, we identify a recurrent MDR-associated spatial nexus along the tumor-stroma interface. This niche juxtaposes CXCL14+ inflammatory cancer-associated fibroblasts (iCAFs), TREM2+ tumor-associated macrophages (TAMs), and AXL+ dedifferentiated tumor cells, and is accompanied by loss of tumor-reactive CXCL13+CD8+ T cells. In vitro, CXCL14 promotes macrophage migration and TREM2 induction, while TREM2+ TAMs suppress CXCL13+CD8+ T cells via CD86-CTLA4 signaling. TREM2+ TAMs also promote tumor dedifferentiation through oleic acid-driven GAS6-AXL activation. We develop an FAP/TREM2-targeting bispecific antibody to disrupt this spatial nexus and restore therapeutic sensitivity in MDR patient-derived xenograft models with favorable safety.
SN  - 2666-3791
ER  -