Abstract: Colorectal cancer (CRC) is the third most common cancer worldwide and ranks second in terms of mortality globally. The treatment of advanced colorectal cancer still faces severe challenges. Although patients with metastatic colorectal cancer (mCRC) characterized by deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) can benefit significantly from immune checkpoint inhibitor therapy, the majority of patients with microsatellite stable (MSS)/proficient mismatch repair (pMMR) types are highly insensitive to single-agent immunotherapy. Their later-line treatments rely on regimens such as multi-target tyrosine kinase inhibitors, anti-angiogenic drugs, and oral chemotherapy. However, the overall objective response rate of the above-mentioned regimens is low, and the survival benefits of patients have not been fully improved. In recent years, with the in-depth research on the mechanisms of the tumor immune microenvironment in patients with MSS/pMMR CRC, the combination strategy of immunotherapy and targeted therapy has become a key direction to break through the treatment bottleneck for such patients, and has shown objective responses and survival improvements in a number of clinical studies. These treatment approaches include combinations of immunotherapy with anti-angiogenic drugs, epidermal growth factor receptor (EGFR) inhibitors, Histone Deacetylase (HDAC) inhibitors, and MAPK pathway inhibitors, among others. Although the current relevant evidence is mainly from early clinical studies, the combination of immunotherapy and targeted therapy has become one of the most promising directions in the field of MSS/pMMR mCRC treatment. This article systematically reviews the biological basis and clinical research progress of relevant combination strategies, and looks forward to the patient subgroups that may benefit in the future and the research development directions, aiming to provide a theoretical basis and clinical reference for optimizing the individualized treatment model for this large category of patients.