Spatiotemporal multiomics uncover tumor ecosystem dynamics during metastatic colonization
- 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
2026-07-30
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.