PHGDH-High Dormant Tumor Cells Evade Immunity and Drive Metastasis

How disseminated tumor cells (DTC) initiate metastatic colonization and survive in distant organs remains poorly understood, particularly the earliest post-seeding events when most cells are eliminated but a resilient minority persists to drive outgrowth. This window is technically difficult to study because early seeding is clinically inaccessible and the surrounding niche undergoes continuous, spatially coordinated changes. To capture these dynamic events, Sun, Zhong, Liu, Zhang, Wang, Liu, Chen, Guo, and colleagues used spatial and single-cell multi-omics (Stereo-seq, scRNA-seq, snATAC-seq) to build a spatiotemporal atlas of lung metastatic colonization in a hepatocellular carcinoma (HCC) mouse model, alongside matched human samples. Lungs were harvested at nine timepoints spanning 15 minutes to 35 days post-injection, capturing the metastatic cascade from seeding to outgrowth. After DTCs seeded in the lung, neutrophils and natural killer (NK) cells were recruited, and NK-derived IFNγ induced tumor cells to amplify immune recruitment, eliminating most DTCs. A small surviving subset entered a transient dormancy marked by high PHGDH expression, reduced proliferation, and silencing of immune-related genes. Coculture experiments showed that nearby alveolar type 2 (AT2) cells can induce this state. Lineage tracing confirmed that PHGDH-high survivors were the primary source of later macrometastases, a pattern also seen across human HCC and other cancers, where higher PHGDH signatures predicted worse survival. Mechanistically, PHGDH, the rate-limiting enzyme in serine metabolism, increases production of the methyl donor SAM, depositing the repressive histone mark H3K27me3 at chemokine genes and thereby suppressing immune recruitment. Before outgrowth, Cx3cr1-high macrophages remodeled the niche to promote immunosuppression through regulatory T cells and tumor proliferation through IGF1 signaling. Blocking the PHGDH–SAM–H3K27me3 axis restored immune infiltration and suppressed metastatic growth only in immune-competent mice, confirming an immune-dependent mechanism. Overall, the study defines a stepwise mechanism in which rare surviving DTCs evade immunity, enter transient dormancy, and undergo niche remodeling that enables outgrowth, highlighting the PHGDH axis and CX3CR1-high macrophages as therapeutic targets.Sun Y, Zhong Y, Liu S, Zhang Z, Wang C, Liu Y, et al. Spatiotemporal multiomics uncover tumor ecosystem dynamics during metastatic colonization. Science 2026;393:eadz7928.Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.