Unraveling Resistance to Immunotherapy in MSI-High Colorectal Cancer

Simple Summary: Mismatch-repair deficient (dMMR)/microsatellite instability high (MSI-H) cancers encompass a subset of colorectal cancers (CRCs) sensitive to immune checkpoint inhibitors (ICIs). Nevertheless, nearly 30% of patients with dMMR/MSI-H CRC show primary resistance to ICIs, and some develop resistance in the course of disease. In this review, we first explore cells involved in immunogenicity and how intracellular and extracellular factors might influence responses to ICIs. Lastly, we depict uncertainties in the diagnosis of dMMR/MSI-H CRC and outline possible approaches to overcome resistance mechanisms.Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths. Incidences of early CRC cases are increasing annually in high-income countries, necessitating effective treatment strategies. Immune checkpoint inhibitors (ICIs) have shown significant clinical efficacy in various cancers, including CRC. However, their effectiveness in CRC is limited to patients with mismatch-repair-deficient (dMMR)/microsatellite instability high (MSI-H) disease, which accounts for about 15% of all localized CRC cases and only 3% to 5% of metastatic CRC cases. However, the varied response among patients, with some showing resistance or primary tumor progression, highlights the need for a deeper understanding of the underlying mechanisms. Elements involved in shaping the response to ICIs, such as tumor microenvironment, immune cells, genetic changes, and the influence of gut microbiota, are not fully understood thus far. This review aims to explore potential resistance or immune-evasion mechanisms to ICIs in dMMR/MSI-H CRC and the cell types involved, as well as possible pitfalls in the diagnosis of this particular subtype.