Spatiotemporal multiomics uncover tumor ecosystem dynamics during metastatic colonization.

Authors

Yunfan Sun, Yu Zhong, Shang Liu, Zefan Zhang, Chunqing Wang, Yang Liu, Junbing Chen, Wei Guo, Xiaoying Gu, Keqiang Rao, Zifei Wang, Muzi Cao, Yue Wang, Waidong Huang, Xuanxuan Zou, Xi Chen, Shuangjian Qiu, Yinhong Shi, Huichuan Sun, Xiaohu Huang, Yuhang Wang, Jiyan Wang, Zhifang Wu, Ru Tian, Yuanhang Zhang, Jie Gu, Miaomiao Jiang, Yinqi Bai, Guibo Li, Min Xie, Feng Xi, Lihua Peng, Shiping Liu, Shuang Yang, Yu Zhang, Miguel A Esteban, Xin Jin, Ao Chen, Jian Wang, Yong Cang, David H Peng, Xun Xu, Jian Zhou, Liang Wu, Jia Fan

Published in

Science (New York, N.Y.). Volume 393. Issue 6810. Pages eadz7928. Jul 30, 2026. Epub Jul 30, 2026.

Abstract

The mechanisms underlying the interactions between disseminated tumor cells (DTCs) and their tissue microenvironment during metastatic colonization are currently poorly understood. We integrated multimodal single-cell and spatial profiling from liver cancer mouse models and human metastases to track the spatiotemporal dynamics of DTCs and their microenvironments from single-cell seeding to overt lung metastasis. We identified a residual population of quiescent Phgdh^high DTCs that survived initial innate immune clearance and became transiently enriched in micrometastases. These cells shaped an immune-scarce microenvironment through PHGDH-dependent, H3K27me3-mediated epigenetic silencing of chemokine transcription, thereby promoting metastatic expansion. Cx3cr1^high interstitial macrophages were also transiently enriched before DTC expansion, creating an immune-privileged niche for metastatic outgrowth by recruiting immunosuppressive cells. Inactivating the PHGDH-H3K27me3 axis in DTCs or depleting interstitial macrophages restored immune surveillance and inhibited metastatic colonization. These findings provide insights into the development of micrometastasis-targeting regimens.

PMID:
42531396
Bibliographic data and abstract were imported from PubMed on 31 Jul 2026.

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