ミスマッチ修復欠損またはマイクロサテライト不安定大腸がんにおける免疫チェックポイント阻害剤への耐性の探索

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.