Abstract 6460: Spatiotemporal multi-omics uncover tumor ecosystem dynamics driving metastatic colonization

The mechanisms underlying the interaction between disseminated tumor cells (DTCs) and their tissue microenvironment during metastasis colonization are 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 across nine sequential time points from single-cell seeding until overt lung metastasis. We identified a residual population of quiescent Phgdhhigh DTCs that survive initial innate immune clearance and become transiently enriched in micrometastases. These cells shape an immune-scarce microenvironment through PHGDH-dependent, H3K27me3-mediated epigenetic silencing of chemokine transcription, promoting metastatic expansion. Cx3cr1high interstitial macrophages were also found to be transiently enriched before DTCs 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 new therapeutic concepts for developing micrometastasis-targeting regimens. Citation Format: Liang Wu, Yu Zhong, Shang Liu, chunqing wang, Zefan zhang, Yunfan Sun, Jian zhou, Jia Fan, Xun xu. Spatiotemporal multi-omics uncover tumor ecosystem dynamics driving metastatic colonization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6460.