Single-cell and spatial transcriptome profiling identifies the immunosuppressive spatial niche in KRAS-mutant colorectal cancer.

BACKGROUND: KRAS is one of the most frequently mutated genes in colorectal cancer (CRC) and plays a crucial role in tumorigenesis, progression, immune evasion, and treatment resistance. The pronounced heterogeneity within KRAS-mutant CRC highlights the urgent need for more precise and personalized therapeutic approaches. METHODS: To investigate this heterogeneity, we employed single-cell RNA sequencing and spatial transcriptomics to comprehensively characterize the tumor microenvironment of KRAS-mutant CRC. Data preprocessing and clustering were performed using Scanpy. Spatial cell-type deconvolution was conducted via Cell2location, whereas intercellular communication and spatial dependencies were analyzed using CellChat, MISTy, and stLearn. RESULTS: Our analyses revealed that KRAS-mutant tumor epithelial cells recruit Mono_S100A8 monocytes via the MDK_SDC4 signaling axis. Concurrently, surrounding Fib_CTHRC1 fibroblasts secrete collagen, which interacts with integrin receptors on KRAS-mutant epithelial cells and contributes to the exclusion of lymphocyte infiltration. CONCLUSION: These cellular components collaboratively established an immunosuppressive spatial niche. These findings offer novel theoretical insights and potential targets for the development of immunoregulatory strategies tailored to KRAS-mutant CRC.