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[Primary resistance mechanisms of immune checkpoint inhibitors in cancer]

Xuhong Chen1, Shuaiting Liu1, Dongxian Tan1

  • 1Medical Research Center, Southern University of Science and Technology Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China.

Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi = Chinese Journal of Cellular and Molecular Immunology
|January 8, 2026
PubMed

Insights

Immune checkpoint inhibitors (ICIs) show promise in cancer treatment but face primary resistance. Understanding resistance mechanisms is key to developing effective combination therapies for broader patient benefit.

Area of Science:

  • Oncology
  • Immunology
  • Cancer Research

Background:

  • Immune checkpoint inhibitor (ICI) therapy represents a significant advancement in cancer treatment, enhancing anti-tumor immune responses and improving patient survival.
  • Despite successes, a substantial proportion of cancer patients exhibit primary resistance to ICI therapy, limiting its widespread clinical benefit.

Purpose of the Study:

  • To systematically review the molecular mechanisms underlying primary resistance to immune checkpoint inhibitors (ICIs).
  • To identify potential therapeutic targets and inform the development of novel combination strategies to overcome ICI resistance in cancer.

Main Methods:

  • Comprehensive literature review focusing on molecular mechanisms of primary ICI resistance.
  • Analysis of key aspects including tumor lymphocyte infiltration, interferon signaling, antigen presentation, and oncogenic signaling pathways.

Main Results:

  • Primary resistance to ICIs is multifactorial, involving tumor microenvironment characteristics and intrinsic tumor cell signaling.
  • Specific molecular pathways such as altered lymphocyte infiltration, impaired interferon signaling, defective antigen presentation, and activated oncogenic pathways contribute to resistance.

Conclusions:

  • Elucidating the molecular basis of primary ICI resistance is crucial for advancing cancer immunotherapy.
  • Identifying novel therapeutic targets within these resistance pathways can guide the development of effective combination strategies to improve patient outcomes.

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