Resistance Phenotypes and Treatment Sequencing After Immune Checkpoint Blockade in MSI-H/dMMR Metastatic Colorectal Cancer: A Review.

Immune checkpoint inhibitors (ICIs) have transformed microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer, but clinically relevant progression still occurs and treatment after progression remains undefined. We performed a clinically oriented narrative review, updated August 8, 2026, and separated direct prospective evidence, retrospective post-ICI evidence, extrapolation from general metastatic colorectal cancer trials, case-level evidence, and biological rationale. In the absence of prospective post-dual-ICI sequencing studies, we propose an evidence-informed conceptual framework. Apparent early progression should prompt confirmation of MSI/MMR status and exclusion of pseudoprogression before classification as early global progression, late systemic progression, or oligoprogression. BRAF V600E is common in MSI-H/dMMR metastatic colorectal cancer and is not an absolute predictor of ICI failure, but it is a major treatment-defining branch after progression. Repeat tissue biopsy or circulating tumor DNA profiling should be selective, used when findings can alter management and without delaying urgent therapy. ctDNA-based molecular residual disease is prognostic after curative-intent colorectal cancer resection, including metastasectomy, but is not validated to direct treatment of radiographically evident post-ICI progression. Oligoprogression warrants multidisciplinary consideration of local therapy, while ICI rechallenge remains investigational. Most recommendations are retrospective or extrapolated; transparent evidence boundaries and prospective post-dual-ICI studies are essential.