Immunosurveillance Shapes the Genetic and Immunogenic Landscape of Mismatch Repair-Deficient Colorectal Tumors
Mismatch repair-deficient (MMRd) colorectal cancers (CRCs) exhibit high mutation burden and frequent immune infiltration, yet often evade immune control. Using a genetically engineered mouse model (VCMsh2), we show that immunosurveillance suppresses tumor initiation but not growth, and selectively eliminates tumors bearing immunogenic mutations. Immunodeficient mice developed more tumors with increased mutational diversity, including recurrent alterations in Ctnnb1, Asxl1, and Rgs12. These mutations were absent in tumors from immunocompetent hosts and elicited CD8? T cell responses in peptide immunization assays, confirming their immunogenicity. Despite their high neoantigen load, MMRd tumors exhibited local immune suppression, marked by reduced cytotoxic cell infiltration and elevated immune checkpoint proteins expression. Our results reveal dual mechanisms of immune escape, immunoediting and microenvironmental immune suppression, and underscore the importance of host-tumor interactions in shaping MMRd CRC evolution. These findings offer mechanistic insights into immune evasion and inform rational design of neoantigen-targeted therapies in hypermutated cancers.