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Immunotherapy Resistance in dMMR/MSI-H Colorectal Cancer: Unraveling Mechanisms and Exploring Overcoming Strategies

Ke Zhou1,2,3, Ping Lu1,2,3, Hongli Xu1,2,3

  • 1Department of Abdominal Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430079, Hubei, China, hust.edu.cn.

Journal of Immunology Research
|August 13, 2026
PubMed

Insights

Immune checkpoint inhibitors (ICIs) face resistance in mismatch repair deficient/high microsatellite instability colorectal cancer (dMMR/MSI-H CRC). Understanding tumor-intrinsic factors and the tumor microenvironment is key to developing new therapies for this cancer.

Area of Science:

  • Oncology
  • Immunotherapy
  • Cancer Biology

Background:

  • Colorectal cancer (CRC) is a major global health concern.
  • Mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H) characterizes a subset of CRC cases.
  • Immune checkpoint inhibitors (ICIs) show efficacy in dMMR/MSI-H CRC but face primary and acquired resistance.

Purpose of the Study:

  • To review the mechanisms of ICI resistance in dMMR/MSI-H CRC.
  • To explore novel therapeutic strategies to overcome resistance.
  • To provide a roadmap for advancing precision immunotherapy in this patient population.

Main Methods:

  • Literature review synthesizing mechanisms of ICI resistance.
  • Analysis of tumor-intrinsic alterations (antigen presentation, signaling pathways, epigenetics).
  • Exploration of the immunosuppressive tumor microenvironment (TME) and emerging therapeutic targets.

Main Results:

  • Tumor-intrinsic factors like defects in antigen presentation (TAP1/2, β2m), Wnt/β-catenin and JAK/STAT signaling, and ARID1A epigenetic remodeling contribute to resistance.
  • An immunosuppressive TME, characterized by T-cell exclusion and myeloid-derived suppressor cells (MDSCs), impedes ICI efficacy.
  • Novel therapies including next-generation ICIs (LAG-3, TIM-3, TIGIT), bispecific antibodies (BsAbs), and adoptive cell transfer show promise.

Conclusions:

  • Overcoming ICI resistance in dMMR/MSI-H CRC requires addressing both tumor-intrinsic and TME-related barriers.
  • Emerging biomarkers like gut microbiome and ctDNA dynamics may guide treatment strategies.
  • Integrating mechanistic insights with novel therapeutic approaches is crucial for improving patient outcomes in dMMR/MSI-H CRC.
Keywords:
DNA mismatch repair deficient (dMMR)drug resistanceimmune checkpoint inhibitors (ICIs)metastatic colorectal cancer (mCRC)microsatellite instability-high (MSI-H)

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