Colon cancer immunotherapy has demonstrated efficacy in certain subtypes, notably those with deficient DNA mismatch repair (dMMR), while patients with proficient DNA mismatch repair (pMMR) often exhibit resistance to immunotherapeutic interventions. To elucidate the underlying mechanisms driving the resistance of pMMR colon cancer patients to immunotherapy, we conducted a comprehensive analysis utilizing single-cell RNA sequencing (scRNA-seq) data from 100 colorectal cancer (CRC) patients encompassing both dMMR and pMMR subtypes. The data is downloaded from open-access resources. Our study aims to employ systems biology methodologies to dissect the molecular differences between dMMR and pMMR CRC patients, with a particular focus on identifying immune regulatory pathways and characterizing ligand-receptor interactions associated with the lack of response to immunotherapy in pMMR patients. By leveraging scRNA-seq data, we aim to delineate cell type-specific alterations in the tumor microenvironment and uncover novel immune evasion mechanisms unique to the pMMR subtype. Through integrative analysis of transcriptomic profiles, pathway enrichment, and network analysis, we seek to unravel key signaling cascades and immune checkpoints that contribute to immunotherapy resistance in pMMR CRC. Furthermore, we aim to identify potential therapeutic targets specific to pMMR patients, offering new avenues for precision medicine interventions. This research holds promise for advancing our understanding of immune evasion mechanisms in colon cancer and may lead to the discovery of novel therapeutic targets tailored to pMMR CRC patients, ultimately improving treatment outcomes and patient survival.