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

Xiaoya Pei; Zhichao Liu; Lin Tang; Junpeng Zhang; Yan He; Xiaowan Zhuang; Yuxiang Song; Shaocong Peng; Yahui Zhao; Xuanzhang Huang; Yiwei Xu; Junyi Li; Liang Peng; Xingyuan Shi; Fan Zhang; Chong Liu; Mingliang He; Wei Dai; Liang Wu; Simon Law; Jinbao Liu; Zhenning Wang; Zhigang Li; Wenwen Xu; Zhihua Liu; Bin Li

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 (Co-first Author), Zhichao Liu (Co-first Author), Lin Tang (Co-first Author), Junpeng Zhang (Co-first Author), Yan He, Xiaowan Zhuang, Yuxiang Song, Shaocong Peng, Yahui Zhao, Xuanzhang Huang, Yiwei Xu, Junyi Li, Liang Peng, Xingyuan Shi, Fan Zhang, Chong Liu, Mingliang He, Wei Dai, Liang Wu, Simon LawJinbao Liu, Zhenning Wang^*, Zhigang Li^*, Wenwen Xu^*, Zhihua Liu^*, Bin Li^*

^*Corresponding author for this work

Department of Biomedical Sciences

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

2 Citations (Scopus)

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. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.

Original language	English
Pages (from-to)	2494-2508
Journal	Nature Genetics
Volume	57
Issue number	10
Online published	10 Oct 2025
DOIs	https://doi.org/10.1038/s41588-025-02341-9
Publication status	Published - Oct 2025

Funding

This work was supported by the National Natural Science Foundation of China (no. 82273141 to B.L., no. 82273368 to W.W.X. and no. 82073196 to W.W.X.), the Outstanding Youth Program of Guangdong Natural Science Research (no. 2023B1515020012 to W.W.X.), the Guangdong Natural Science Research International joint project (no. 2023A0505050165 to B.L.), the Science and Technology Program of Guangzhou (no. 2023A03J0425 to B.L. and no. 2025A03J3288 to F.Z.), the Guangzhou Education Bureau Yangcheng Scholar Research Project (no. 202235385 to B.L.), the Key Laboratory of Guangdong Higher Education Institutes (no. 2021KSYS009 to B.L.) and the key disciplines of medicine of Guangzhou (no. 2025-2027 to B.L.).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Access Output

10.1038/s41588-025-02341-9

Other Access Options

Check CityUHK Library

Permanent Link

Right click to copy link

Cite this

Pei, X., Liu, Z., Tang, L., Zhang, J., He, Y., Zhuang, X., Song, Y., Peng, S., Zhao, Y., Huang, X., Xu, Y., Li, J., Peng, L., Shi, X., Zhang, F., Liu, C., He, M., Dai, W., Wu, L., ... Li, B. (2025). Single-cell multi-omic and spatial profiling of esophageal squamous cell carcinoma reveals the immunosuppressive role of GPR116⁺ pericytes in cancer metastasis. Nature Genetics, 57(10), 2494-2508. https://doi.org/10.1038/s41588-025-02341-9

@article{6493074984b34738b1685d95bf33f93c,

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

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. {\textcopyright} The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.",

author = "Xiaoya Pei and Zhichao Liu and Lin Tang and Junpeng Zhang and Yan He and Xiaowan Zhuang and Yuxiang Song and Shaocong Peng and Yahui Zhao and Xuanzhang Huang and Yiwei Xu and Junyi Li and Liang Peng and Xingyuan Shi and Fan Zhang and Chong Liu and Mingliang He and Wei Dai and Liang Wu and Simon Law and Jinbao Liu and Zhenning Wang and Zhigang Li and Wenwen Xu and Zhihua Liu and Bin Li",

year = "2025",

month = oct,

doi = "10.1038/s41588-025-02341-9",

language = "English",

volume = "57",

pages = "2494--2508",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Springer Nature",

number = "10",

}

Pei, X, Liu, Z, Tang, L, Zhang, J, He, Y, Zhuang, X, Song, Y, Peng, S, Zhao, Y, Huang, X, Xu, Y, Li, J, Peng, L, Shi, X, Zhang, F, Liu, C, He, M, Dai, W, Wu, L, Law, S, Liu, J, Wang, Z, Li, Z, Xu, W, Liu, Z & Li, B 2025, 'Single-cell multi-omic and spatial profiling of esophageal squamous cell carcinoma reveals the immunosuppressive role of GPR116⁺ pericytes in cancer metastasis', Nature Genetics, vol. 57, no. 10, pp. 2494-2508. https://doi.org/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. / Pei, Xiaoya (Co-first Author); Liu, Zhichao (Co-first Author); Tang, Lin (Co-first Author) et al.
In: Nature Genetics, Vol. 57, No. 10, 10.2025, p. 2494-2508.

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

TY - JOUR

T1 - Single-cell multi-omic and spatial profiling of esophageal squamous cell carcinoma reveals the immunosuppressive role of GPR116+ pericytes in cancer metastasis

AU - Pei, Xiaoya

AU - Liu, Zhichao

AU - Tang, Lin

AU - Zhang, Junpeng

AU - He, Yan

AU - Zhuang, Xiaowan

AU - Song, Yuxiang

AU - Peng, Shaocong

AU - Zhao, Yahui

AU - Huang, Xuanzhang

AU - Xu, Yiwei

AU - Li, Junyi

AU - Peng, Liang

AU - Shi, Xingyuan

AU - Zhang, Fan

AU - Liu, Chong

AU - He, Mingliang

AU - Dai, Wei

AU - Wu, Liang

AU - Law, Simon

AU - Liu, Jinbao

AU - Wang, Zhenning

AU - Li, Zhigang

AU - Xu, Wenwen

AU - Liu, Zhihua

AU - Li, Bin

PY - 2025/10

Y1 - 2025/10

N2 - 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. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.

AB - 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. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.

UR - http://www.scopus.com/inward/record.url?scp=105018398353&partnerID=8YFLogxK

UR - https://www.scopus.com/record/pubmetrics.uri?eid=2-s2.0-105018398353&origin=recordpage

U2 - 10.1038/s41588-025-02341-9

DO - 10.1038/s41588-025-02341-9

M3 - RGC 21 - Publication in refereed journal

C2 - 41073785

SN - 1061-4036

VL - 57

SP - 2494

EP - 2508

JO - Nature Genetics

JF - Nature Genetics

IS - 10

ER -