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Traditional and New Views on MSI-H/dMMR Endometrial Cancer.

Chuqi Liu1,2, Huiyu Ping1,2, Mengmeng Yao1,2

  • 1Lin He's Academician Workstation of New Medicine and Clinical Translation, Jining Medical University, Jining 272067, China.

Biomolecules
|October 29, 2025
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Summary

This review explores mismatch repair (MMR) deficient endometrial cancer (EC), highlighting how genetic differences influence immune microenvironments and response to immune checkpoint inhibitors (ICIs). Understanding these variations is key for personalized treatment strategies.

Keywords:
MSI-H/dMMR endometrial cancerbase mismatch repair pathwaynext-generation sequencing

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Area of Science:

  • Oncology
  • Genetics
  • Immunology

Background:

  • Endometrial cancer (EC) with high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR) is linked to the MMR pathway.
  • This cancer type has a distinct immune microenvironment, making it a candidate for immune checkpoint inhibitor (ICI) therapy.
  • dMMR EC presents heterogeneity: Lynch syndrome (LS)-associated, sporadic (MLH1 hypermethylation), and Lynch-like (somatic mutations).

Purpose of the Study:

  • To discuss the role of traditional and nontraditional MMR genes in dMMR EC.
  • To review current treatment strategies for dMMR EC.
  • To enhance understanding of dMMR EC heterogeneity for precision diagnosis and treatment.

Main Methods:

  • Literature review of dMMR endometrial cancer.
  • Analysis of genetic mutations in MMR genes (traditional and nontraditional).
  • Examination of immune microenvironment differences across dMMR EC subtypes.

Main Results:

  • Subtypes of dMMR EC (LS-associated, sporadic, Lynch-like) exhibit varying immune microenvironments, potentially impacting ICI efficacy.
  • The impact of somatic mutations in traditional MMR genes on EC is often overlooked.
  • Over 50% of MSI patients do not respond to ICIs, possibly due to nontraditional MMR gene abnormalities.

Conclusions:

  • dMMR EC heterogeneity, including genetic variations in MMR genes, significantly influences therapeutic responses.
  • Addressing overlooked genetic factors and understanding subtype-specific immune profiles are crucial for improving ICI efficacy.
  • Enhanced understanding of dMMR EC heterogeneity will advance precision diagnosis and treatment strategies.