The lung is one of the most common sites of distant metastasis for many malignancies. However, how the lung metastatic niche evolves during disease progression, and whether lung metastases from different primary tumors share common immune features, remain poorly understood.

A collaborative study led by Zemin Zhang at the Biomedical Pioneering Innovation Center (BIOPIC), Peking University, Lai Guan Ng at Westlake University, and Huijuan Wu at Shanghai Jiao Tong University School of Medicine was recently published online as a cover article in Genes & Diseases, entitled “Dynamic single-cell landscape reveals a T-cell-suppressed microenvironment and a conserved neutrophil program in the lung metastatic niche.”

Figure 1. Cover illustration. Lung metastases establish a T-cell-suppressed, neutrophil-dominated immune environment distinct from primary lung tumors. STEAP4⁺ neutrophils can also be detected in peripheral blood, highlighting their potential as a blood-based marker.

By integrating human tumor transcriptomes, longitudinal single-cell sequencing across multiple mouse models, tissue imaging, and peripheral blood analyses, the researchers identified a distinct population of STEAP4⁺ neutrophils highly specific to lung metastasis. These cells emerged early, accumulated with metastatic progression in mouse models, and were detectable in patients’ peripheral blood, highlighting their potential as a blood-based marker for lung metastasis. The study also revealed a shared immune remodeling trajectory characterized by suppression of T-cell activation and progressive myeloid-cell dominance.

A shared immune microenvironment across lung metastases

Transcriptomic analysis of human tumors showed that lung metastases from multiple primary cancers consistently exhibited reduced T-cell activation and effector programs compared with primary lung tumors.

Longitudinal single-cell profiling of more than 200,000 cells further revealed distinct immune trajectories: primary lung tumors maintained a lymphocyte-engaged environment, whereas lung metastases remained T-cell-suppressed and progressively became dominated by neutrophils and monocytes. Similar patterns were observed in melanoma and rhabdomyosarcoma models, identifying T-cell suppression and myeloid-cell dominance as shared microenvironmental features of lung metastasis.

A conserved neutrophil program identifies STEAP4⁺ neutrophils as a potential blood-based marker

Neutrophils showed the most rapid and pronounced expansion during lung metastasis and became the predominant immune population at advanced stages. Single-cell analysis identified two neutrophil states selectively enriched in metastatic lungs: an early MN_E state and a late MN_L state. These populations were virtually absent from normal lungs, primary lung tumors, and primary mammary tumors. These neutrophils were marked by high expression of Steap4, Mif, Cstdc6, and Stfa2.

Figure 2. Selective enrichment of metastatic neutrophils in lung metastatic niche.

Based on these cells, the researchers constructed a 65-gene metastasis-specific neutrophil signature, termed MNsig. MNsig was consistently detected across models of breast cancer, melanoma, and rhabdomyosarcoma, indicating a conserved neutrophil program associated with lung metastatic progression.

Screening MNsig genes encoding cell-surface proteins identified STEAP4 as the leading candidate marker. Across four independent mouse models, STEAP4 distinguished 17 lung metastasis samples from 14 normal lung samples with an area under the receiver operating characteristic curve of 0.938, outperforming candidate Myeloid-derived suppressor cell markers including CD14, PD-L1, and CD300LD.

Tissue staining showed that STEAP4⁺ neutrophils were rare in normal lungs and primary lung tumors but appeared during early metastasis and accumulated with disease progression in MMTV-PyMT model. They were also enriched in human lung metastases originating from breast and renal cancers.

Importantly, STEAP4⁺ neutrophils were detectable in peripheral blood. They accounted for an average of approximately 0.78%, 0.73%, and 1.45% of circulating neutrophils in healthy donors, patients with primary lung cancer, and patients with localized breast cancer, respectively. In seven patients with breast cancer lung metastasis, however, their average proportion reached 43%—approximately 30-fold higher than in patients with localized breast cancer.

Figure 3. Selective enrichment of STEAP4⁺ neutrophils in peripheral blood of mouse models (A) and humans (B-C).

Research significance

Neutrophils are abundant in the circulation and highly responsive to tissue changes. Detecting circulating STEAP4⁺ neutrophils may therefore offer a more accessible monitoring strategy that does not rely on rare circulating tumor cells or tumor-specific mutations. These findings support STEAP4⁺ neutrophils as a potential blood-based marker for lung metastasis and provide a new direction for future early-detection and longitudinal-monitoring studies.

The current clinical cohort remains small, and larger multicenter studies will be needed to establish diagnostic sensitivity and specificity, particularly in the presence of infection or inflammation. The functional role of STEAP4⁺ neutrophils in metastatic progression also remains to be determined.

This study was conducted by researchers from Peking University, Westlake University, Shanghai Jiao Tong University School of Medicine, Shanghai Pulmonary Hospital, and collaborating institutions. Chen Ai, Huijuan Wu, Huihui Yang, and Jing Wang are co-first authors. Zemin Zhang, Lai Guan Ng, and Huijuan Wu are co-corresponding authors. Melissa S.F. Ng, Chang Chen, Zhaode Bu, and Lingqian Wang also made important contributions.

Original article: https://doi.org/10.1016/j.gendis.2026.102214

Interactive data portal: http://lungmet.cancer-pku.cn/