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

Mastel, M.; Guiseris Martinez, A.; Diamante, G.; Meier, J.; Schuchmann, L.; Georgakopoulos, N.; Chiotakakos, I.; Steffens, L. K.; Artmann, C.; Benitez, D.; Guenther, M.; Thiel, V.; Pincheira, R.; Trumpp, A.; Offringa, R.; Ormanns, S.; Jackstadt, R.

2026-01-09 cancer biology
10.64898/2026.01.09.697991 bioRxiv
Show 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-{gamma} 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.

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