Harnessing mismatch repair deficiency for therapeutic targeting in cancers

MMRd is currently recognized a tumor-agnostic biomarker for ICI treatment. However, differences in the MMRd etio-biology impact the immune microenvironment, contributing to significant response heterogeneity. Some patients show dramatic response to neoadjuvant ICI monotherapy and don't even need surgery, while most will need biologically rational combination approaches. Additionally, MMRd-driven genomic instability can make this a 'moving target,' mandating an ongoing effort to track and adapt to MMRd-driven cancer and microenvironment evolution. The next decade will focus on how best to effectively tailor immune-directed therapies for different MMRd cancers.