MICROMETASTASIS development has been driven by quiescent disseminated tumour cells that suppressed immune surveillance and established an immune privileged environment, according to a multimodal study using mouse models and human metastatic samples.
Researchers combined single cell and spatial profiling techniques to investigate how disseminated tumour cells interacted with their surrounding tissue during metastatic colonisation. The analysis tracked disease progression from single disseminated tumour cells through to established lung metastases, providing a detailed view of the changing tumour microenvironment over time.
The study identified a residual population of quiescent disseminated tumour cells with high phosphoglycerate dehydrogenase expression that survived initial innate immune clearance. These cells became transiently enriched during the micrometastatic stage before overt metastatic expansion, suggesting they play a pivotal role in the earliest phases of metastatic growth.
Investigators found that phosphoglycerate dehydrogenase activity promoted an immune scarce microenvironment through histone H3 lysine 27 trimethylation mediated epigenetic silencing of chemokine transcription. This reduced immune cell recruitment and enabled disseminated tumour cells to expand within metastatic sites.
The researchers also identified a transient increase in Cx3cr1 high interstitial macrophages before tumour cell expansion. These macrophages contributed to an immune privileged niche by recruiting immunosuppressive cells, further limiting immune surveillance during metastatic colonisation.
Together, the findings suggested that both tumour intrinsic and microenvironmental mechanisms cooperated to protect disseminated tumour cells during the critical transition from micrometastasis to overt metastatic disease.
The investigators evaluated strategies to disrupt these immune evasion pathways in preclinical models. Inactivation of the phosphoglycerate dehydrogenase and histone H3 lysine 27 trimethylation signalling axis within disseminated tumour cells restored immune surveillance and inhibited metastatic colonisation. Similarly, depletion of interstitial macrophages prevented formation of the immune privileged niche and reduced metastatic outgrowth.
The authors concluded that the study provides new insight into the cellular and molecular events underpinning micrometastasis. By identifying mechanisms that allow disseminated tumour cells to evade immune clearance during the earliest stages of metastatic colonisation, the findings highlight potential therapeutic approaches aimed at preventing metastatic progression before clinically detectable secondary tumours develop.
Reference
Sun Y et al. Spatiotemporal multiomics uncover tumor ecosystem dynamics during metastatic colonization. Science. 2026;393(6810):eadz7928
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