Single-cell multi-omic and spatial profiling of esophageal squamous cell carcinoma reveals the immunosuppressive role of GPR116⁺ pericytes in cancer metastasis

Xiaoya Pei^#¹, Zhichao Liu^#², Lin Tang^#³, Junpeng Zhang^#⁴, Yan He³, Xiaowan Zhuang¹, Yuxiang Song³, Shaocong Peng¹, Yan He¹, Yahui Zhao⁵, Xuanzhang Huang⁶, Yiwei Xu⁷, Junyi Li¹, Liang Peng⁸, Xingyuan Shi⁹, Fan Zhang¹⁰, Chong Liu¹¹, Mingliang He¹², Wei Dai¹³, Liang Wu⁴, Simon Law¹⁴, Jinbao Liu³, Zhenning Wang¹⁵, Zhigang Li¹⁶, Wenwen Xu¹⁷, Zhihua Liu¹⁸, Bin Li¹⁹

Affiliations

¹ State Key Laboratory of Respiratory Disease, Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
² Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
³ State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, The Affiliated Traditional Chinese Medicine Hospital, Guangzhou Medical University, Guangzhou, China.
⁴ BGI Research, Chongqing, China.
⁵ State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
⁶ Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China.
⁷ Department of Clinical Laboratory Medicine, Esophageal Cancer Prevention and Control Research Center, Cancer Hospital of Shantou University Medical College, Shantou, China.
⁸ The Fifth Affiliated Hospital of Guangzhou Medical University, KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, China.
⁹ Department of Radiation Oncology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
¹⁰ Department of Gastrointestinal Surgery, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
¹¹ Department of Neurosurgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
¹² Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China.
¹³ Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
¹⁴ Department of Surgery, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
¹⁵ Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China. znwang@cmu.edu.cn.
¹⁶ Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China. zhigang.li@shsmu.edu.cn.
¹⁷ State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, The Affiliated Traditional Chinese Medicine Hospital, Guangzhou Medical University, Guangzhou, China. xuwen6966@163.com.
¹⁸ State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. liuzh@cicams.ac.cn.
¹⁹ State Key Laboratory of Respiratory Disease, Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China. lib2128@163.com.

^# Contributed equally.

PMID: 41073785
DOI: 10.1038/s41588-025-02341-9

Single-cell multi-omic and spatial profiling of esophageal squamous cell carcinoma reveals the immunosuppressive role of GPR116⁺ pericytes in cancer metastasis

Xiaoya Pei et al. Nat Genet. 2025 Oct.

. 2025 Oct;57(10):2494-2508.

doi: 10.1038/s41588-025-02341-9. Epub 2025 Oct 10.

Authors

Affiliations

¹ State Key Laboratory of Respiratory Disease, Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
² Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
³ State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, The Affiliated Traditional Chinese Medicine Hospital, Guangzhou Medical University, Guangzhou, China.
⁴ BGI Research, Chongqing, China.
⁵ State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
⁶ Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China.
⁷ Department of Clinical Laboratory Medicine, Esophageal Cancer Prevention and Control Research Center, Cancer Hospital of Shantou University Medical College, Shantou, China.
⁸ The Fifth Affiliated Hospital of Guangzhou Medical University, KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, China.
⁹ Department of Radiation Oncology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
¹⁰ Department of Gastrointestinal Surgery, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
¹¹ Department of Neurosurgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
¹² Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China.
¹³ Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
¹⁴ Department of Surgery, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
¹⁵ Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China. znwang@cmu.edu.cn.
¹⁶ Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China. zhigang.li@shsmu.edu.cn.
¹⁷ State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, The Affiliated Traditional Chinese Medicine Hospital, Guangzhou Medical University, Guangzhou, China. xuwen6966@163.com.
¹⁸ State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. liuzh@cicams.ac.cn.
¹⁹ State Key Laboratory of Respiratory Disease, Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China. lib2128@163.com.

^# Contributed equally.

PMID: 41073785
DOI: 10.1038/s41588-025-02341-9

Abstract

Tumor metastasis leads to most cancer deaths. However, how cellular diversity and dynamic cooperation within the tumor microenvironment contribute to metastasis remains poorly understood. Here we leverage single-cell multi-omics (16 samples, 117,169 cells) and spatial transcriptomics (five samples, 195,366 cells) to uncover the cellular and spatial architecture of esophageal squamous cell carcinoma (ESCC), and characterize an immunosuppressive GPR116⁺ pericyte subset promoting tumor metastasis and immunotherapy resistance. GPR116⁺ pericyte enrichment is transcriptionally regulated by PRRX1, evidenced by pericyte-specific Prrx1 knockout mice. Mechanistically, GPR116⁺ pericytes secrete EGFL6 to bind integrin β1 on cancer cells, activating the NF-κB pathway to facilitate metastasis. Serum EGFL6 serves as a noninvasive biomarker for the diagnosis and prognosis of several tumors. Blocking integrin β1 suppresses metastasis and improves immunotherapy response in animal models of ESCC. Collectively, we provide a spatially resolved landscape of the prometastatic tumor microenvironment in ESCC and highlight the biological and clinical importance of GPR116⁺ pericytes, proposing potential innovative therapeutic strategies for metastatic cancers.

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Conflict of interest statement

Competing interests: The authors declare no competing interests.

References

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Single-cell multi-omic and spatial profiling of esophageal squamous cell carcinoma reveals the immunosuppressive role of GPR116⁺ pericytes in cancer metastasis

Affiliations

Single-cell multi-omic and spatial profiling of esophageal squamous cell carcinoma reveals the immunosuppressive role of GPR116⁺ pericytes in cancer metastasis

Authors

Affiliations

Abstract

Conflict of interest statement

References

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