Single-cell characterization of tumor immune landscapes in colorectal cancer humanized mice

Colorectal cancer (CRC) displays inter-patient heterogeneity in molecular tumor features and immune cell composition, which influence therapy response. Humanized immune system (HIS) mouse models offer a promising in vivo model to study human tumor-immune interactions, yet their ability to recapitulate the CRC tumor immune microenvironment at single-cell resolution remains incompletely defined. Here, we performed single-cell RNA sequencing of systemic and tumor-infiltrating human immune cells in HIS mice bearing human CRC tumors and benchmarked these data against reference datasets of healthy human spleens and primary CRC tumors. Major immune lineages and transcriptional programs characteristic of the human systemic immune compartment were identified, and HIS mouse tumors developed complex, human-like immune infiltrates. Tumor-infiltrating immune cells comprised diverse T cell, myeloid, natural killer, and B cell populations, including exhausted T cell states marked by expression of PDCD1, TIGIT, HAVCR2, LAG3, and CTLA4. We further demonstrate CRC consensus molecular subtype-associated spatial differences in immune infiltration. Collectively, our findings support the use of HIS mice as a relevant model for studying CRC immune landscapes and preclinical evaluation of immunomodulatory therapies.