Senescent-Like Neutrophils Shape Angiogenic Immunosuppressive Niches in Colorectal Cancer Liver Metastasis

UNLABELLED: Neutrophils are major players in innate immunity. However, their landscape and functions in colorectal cancer liver metastasis (CRLM) remain poorly understood. In this study, using single-cell RNA sequencing and spatial-enhanced-resolution-omics sequencing, we provide a comprehensive transcriptional landscape of tumor-associated neutrophils (TAN) in CRLM. Our analysis reveals that a terminally differentiated protumor neutrophil subset (TAN1), characterized by a glycolysis signature and a senescent phenotype, is significantly enriched in liver metastasis and associated with poor prognosis. Mechanistically, TAN1 arises from other TAN subsets through the upregulation of BHLHE40, driven by glucose deprivation in the metastatic microenvironment. Functionally, TAN1 promotes angiogenesis via VEGFA and recruits immunosuppressive macrophages through potential CCL3L1-CCR1 signaling, thereby fostering an angiogenic immunosuppressive niche. As a result, neutrophil-specific knockout of Bhlhe40 in mice significantly promotes antitumor immunity and suppresses tumor growth. Our data uncover the critical role of BHLHE40+ senescent-like neutrophils in shaping the immunosuppressive microenvironment of CRLM. SIGNIFICANCE: This study identifies a protumoral BHLHE40+ senescent-like neutrophil subset in CRLM that orchestrates vascular immunosuppressive niches to drive tumor progression, highlighting a potential target for neutrophil-specific therapeutic intervention. See related commentary by Droin and Garner, p. 1958.