Dynamic single-cell landscape reveals a T-cell-suppressed microenvironment and a conserved neutrophil program in the...

While the immune landscape of primary tumors is increasingly understood, the dynamic immune remodeling within the evolving lung metastatic microenvironment remains poorly characterized. Here, by systematically comparing the microenvironments of primary and metastatic tumors using single-cell transcriptomics across diverse cancer models, we reveal that lung metastases consistently establish a profoundly T-cell-suppressed microenvironment. Concurrently, we identified a strictly metastasis-specific neutrophil gene program. Crucially, this program is highly concurrent with the metastatic microenvironment and is fundamentally distinct from neutrophil phenotypes observed in primary tumors or healthy lungs. Among the core genes defining this program, we identified the cell surface marker STEAP4 as a highly specific indicator of these metastasis-associated neutrophils. In both murine models and human patients, these STEAP4⁺ neutrophils were not only enriched within the local lung metastatic niche but also detectable in the circulation. Furthermore, the abundance of circulating STEAP4⁺ neutrophils discriminates breast cancer patients with lung metastasis from those with localized primary tumors or healthy donors. Our findings delineate the divergent immune remodeling trajectories of lung metastasis and highlight their association with STEAP4⁺ neutrophils, establishing a useful biological framework for future functional and mechanistic investigations.