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 CD169^DTR/+Apc^Min/+ 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.