Exploring resistance to immune checkpoints inhibitors in mismatch repair-deficient or microsatellite-instable...

Area of Science:

• Oncology
• Immunotherapy
• Molecular Diagnostics

Background:

• Mismatch-repair deficiency (dMMR) or high microsatellite instability (MSI-H) defines a distinct colorectal cancer (CRC) subtype.
• Immune checkpoint inhibitors (ICIs) are a standard treatment for dMMR/MSI-H CRC, showing durable responses and improved survival.
• Primary or acquired resistance to ICIs occurs in up to one-third of patients, necessitating further research.

Purpose of the Study:

• To review the clinical efficacy of ICIs in dMMR/MSI-H CRC.
• To explore mechanisms underlying ICI resistance in this patient population.
• To identify predictive biomarkers and novel therapeutic strategies to overcome resistance.

Main Methods:

• Comprehensive literature review of clinical trials and preclinical studies.
• Analysis of resistance mechanisms, including intrinsic and extrinsic factors.
• Evaluation of potential predictive biomarkers for ICI response.
• Discussion of emerging therapeutic approaches and combination strategies.

Main Results:

• Established clinical benefit of ICIs in dMMR/MSI-H CRC.
• Identified key mechanisms contributing to primary and acquired resistance.
• Highlighted the potential of various biomarkers to predict treatment response.
• Outlined promising novel therapeutic strategies, including combination therapies.

Conclusions:

• ICIs are highly effective in dMMR/MSI-H CRC, but resistance remains a challenge.
• Understanding resistance mechanisms and identifying predictive biomarkers are crucial for optimizing patient selection.
• Innovative therapeutic strategies, including combination approaches and novel agents, are needed to improve outcomes for all patients with dMMR/MSI-H CRC.