Harnessing mismatch repair deficiency for therapeutic targeting in cancers

INTRODUCTION: Mismatch-repair deficiency (MMRd) is a pan-cancer mechanism resulting in high tumor mutation and microsatellite burden, leading to remarkable therapeutic success using immune checkpoint inhibition (ICI). However, efficacy remains variable. Our goal is to review the existing and emerging literature that provide mechanistic insights on how MMRd diversely impacts the current landscape of cancer therapeutics. AREAS COVERED: We summarize the biological impact of MMRd, highlight how variable etiologies and different MMRd cancer-types have significant diversity in genomic and immune profiles, how this drives primary and acquired ICI-resistance, and highlight the clinical trial landscape and preclinical efforts to harness these distinct mechanistic vulnerabilities into new therapeutic strategies. EXPERT OPINION: 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.