Deficient mismatch repair/microsatellite instability-high colorectal cancer: current treatment paradigms, limitations and future perspectives

The treatment paradigm for deficient mismatch repair (dMMR) colorectal cancer (CRC) has evolved substantially in recent years. Universal mismatch repair testing and broad use of next-generation sequencing have increased the detection of dMMR tumours, which exhibit microsatellite instability-high (MSI-H), hypermutation and abundant neoantigens. The presence of dMMR/MSI-H serves as a robust predictive biomarker for immune checkpoint inhibitor (ICI) therapy, which has demonstrated superior efficacy to cytotoxic chemotherapy in the metastatic setting and led to the first tumour-agnostic Food and Drug Administration approval in 2017 for metastatic dMMR/MSI-H solid tumours. Recent evidence also supports the benefit of ICIs in non-metastatic dMMR CRC. Neoadjuvant immunotherapy has produced high rates of pathological response in both colon and rectal cancers. In locally advanced dMMR rectal cancer, ICI therapy has enabled omission of chemoradiation and surgery in most patients. In resected node-positive dMMR colon cancer, the addition of ICI therapy to chemotherapy has substantially improved disease-free survival, expanding its role earlier in the disease course. Despite these advances, the optimal treatment strategy for non-metastatic dMMR CRC remains undefined due to the lack of direct comparative studies. Importantly, a subset of patients derives limited or no benefit from ICIs despite dMMR/MSI-H status, underscoring the need to further elucidate resistance mechanisms and to develop strategies to overcome them.