Exploring resistance to immune checkpoints inhibitors in mismatch repair-deficient or microsatellite-instable colorectal cancer

Colorectal cancer (CRC) with mismatch-repair deficiency (dMMR) or high microsatellite instability (MSI-H) represents a distinct molecular subtype highly sensitive to immune checkpoint inhibitors (ICIs). Landmark clinical trials have established ICIs as standard-of-care in this setting, demonstrating durable responses and improved survival. However, up to one-third of patients will exhibit primary or acquired resistance, highlighting the urgent need for predictive biomarkers and novel therapeutic strategies. This review summarizes the clinical evidence supporting ICIs in dMMR/MSI-H CRC, explores mechanisms of resistance-including intrinsic and extrinsic modulators-and evaluates the role of potential predictive biomarkers of response. Finally, we discuss innovative therapeutic approaches to overcome resistance, including combination strategies, DNA repair pathway inhibitors, immune-oncology drugs beyond checkpoint inhibitors and microbiome-targeted interventions. Together, these insights aim to refine patient selection, optimize therapeutic benefit, and guide the development of next-generation therapies for dMMR/MSI-H CRC.