CD169 macrophages identify and eliminate tumor cells in colorectal cancer through CD169/CD43 interaction and FasL-driven apoptosis.

Tumor-associated macrophages (TAMs) play key roles in tumor progression and therapy resistance. In colorectal cancer (CRC), TAM heterogeneity challenges macrophage-targeted therapies, with certain antitumor macrophage subpopulations not yet fully characterized. This study bridges this gap by identifying a distinct subset of tumoricidal CD169 macrophages. Increased infiltration of CD169 macrophages was observed in CRC tissues, which was significantly associated with improved overall survival in patients with CRC. Deleting CD169 macrophages in genetically engineered mouse models (MC38 orthotopic/ectopic and CD169Apc intestinal adenoma) accelerated tumor growth. Integrated multi-omics data and functional assays, including cell coculture models and animal experiments with antibody blockade, reveal an antitumor mechanism in which CD169 macrophages directly interact with CRC cells. This interaction, mediated by CD169/CD43 molecular engagements, leads to tumor cell apoptosis via high levels of factor-related apoptosis ligand (FasL). Our results not only deepen our understanding of the CRC tumor microenvironment but also open avenues for cancer immunotherapy targeting.