Abstract: Colorectal cancer (CRC), a common malignant tumor of the digestive system, poses a significant threat to patients' quality of life and prognosis. In recent years, immune checkpoint inhibitor (ICI) therapy has brought breakthroughs for patients with deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) types of CRC. However, the efficacy of ICI therapy in patients with microsatellite stability (MSS) CRC, who account for more than 85% of all CRCs, is significantly limited, which is a clinical dilemma that highlights the importance of in-depth investigation of immunotherapy resistance mechanisms. Existing studies have demonstrated that the microenvironment of MSS-type CRC is characterized by unique immunosuppression, including multidimensional factors, such as defective antigen presentation, infiltration of suppressive immune cells, and dysregulation of the cytokine network. These factors collectively constitute a response barrier to immunotherapy. This review systematically analyzes the key molecular mechanisms of immunoresistance in MSS-type CRC, focusing on the immunosuppressive characteristics of the tumor microenvironment, epigenetic regulatory abnormalities, immune-metabolic reprogramming, gut microbiota imbalance, and other core aspects. The study aims to provide a theoretical basis for breaking through the immunotherapeutic bottleneck of MSS-type intestinal cancer at the mechanistic level and pointing to the potential direction of research on combined therapeutic strategies.