Advances in immune therapies for the treatment of microsatellite instability‑high/deficient mismatch repair metastatic colorectal cancer (Review).

Abstract

Microsatellite instability-high/deficient mismatch repair colorectal cancer (MSI-H/dMMR CRC) is a molecular subtype characterized by high-frequency mutations within DNA mismatch repair genes. Defects in the DNA mismatch repair machinery lead to subsequent frame-shift mutations, resulting in the generation of frame-shift peptides that serve as neoantigens. This has translated into exquisite sensitivity to immune checkpoint inhibitors (ICIs) and a significant clinical benefit from immune therapies in this patient population. The present article provides a comprehensive review of the advances in the field of immune therapies for MSI-H/dMMR metastatic CRC, with a focus on the major randomized clinical trials that led to Food and Drug Administration approval of specific ICIs for this population, a detailed review of the molecular background responsible for tumor response, as well as the mechanisms of resistance to ICI therapy. Finally, ongoing investigations of other immunotherapeutic strategies to address and overcome the challenges that currently limit response and long-term response to ICIs were presented.