Spatiotemporal multiomics uncover tumor ecosystem dynamics during metastatic colonization

Area of Science:

• Oncology
• Cancer Biology
• Immunology

Background:

• Mechanisms of tumor cell-microenvironment interactions in metastasis are poorly understood.
• Disseminated tumor cells (DTCs) face immune clearance and require specific niches for colonization.

Purpose of the Study:

• To investigate the spatiotemporal dynamics of DTCs and their microenvironment during metastatic colonization.
• To identify key cellular and molecular players enabling micrometastasis formation and outgrowth.

Main Methods:

• Integrated multimodal single-cell and spatial profiling in mouse models and human liver metastases.
• Tracking DTCs from single-cell seeding to overt lung metastasis.
• Investigating the role of PHGDH, H3K27me3, and interstitial macrophages in immune evasion.

Main Results:

• Identified a quiescent, *Phgdh*^high DTC population surviving innate immunity and enriching in micrometastases.
• These DTCs epigenetically silenced chemokines via PHGDH-H3K27me3, creating an immune-scarce microenvironment.
• *Cx3cr1*^high interstitial macrophages were transiently enriched, recruiting immunosuppressive cells and promoting immune privilege.
• Inactivating the PHGDH-H3K27me3 axis or depleting interstitial macrophages restored immune surveillance and inhibited metastasis.

Conclusions:

• DTCs actively shape their microenvironment to evade immune detection and promote metastatic expansion.
• The PHGDH-H3K27me3 pathway in DTCs and interstitial macrophages are critical regulators of early metastatic colonization.
• Targeting these mechanisms offers potential therapeutic strategies against micrometastasis.