Genotype-phenotype mapping identifies fetal-like CD55 + immunoregulatory cancer cells as mediators of immune escape in colorectal cancer

Abstract Immune evasion is a defining feature of advanced colorectal cancer (CRC), yet the cellular mechanisms linking cancer cell states to immune suppression remain poorly understood. To systematically map tumour-immune interactions in advanced CRC, we modelled recurrent human CRC mutations using a multiplex CRISPR-based genetically engineered mouse model platform. The resulting 20 models recapitulate key stages, genetic routes and histopathological features of human CRC, while single-cell transcriptomics reveals extensive disease complexity across models. Profiling of the epithelial tumour compartment identified a population of fetal-like immunoregulatory cancer cells (IRCs) characterized by interferon-γ and MAPK activity. IRCs are marked by expression of the membrane-bound complement regulatory protein CD55. Mechanistically, CD55 protects IRCs from immune surveillance and complement-mediated lysis. Together, these findings reveal a cancer cell-immune interface that promotes immune evasion in advanced CRC.