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Regulation of immune checkpoint molecules in cancer immune evasion and therapy

Cansu Eris1, Cheng Zu1,2, Yanling Xiao3

  • 1Division of Immune Regulation in Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Nature Reviews. Cancer
|May 18, 2026
PubMed

Insights

Tumors exploit immune checkpoints to evade the immune system, limiting cancer immunotherapy effectiveness. Understanding multilayered regulation of these checkpoints is key to improving patient outcomes and developing new therapeutic strategies.

Area of Science:

  • Immunology
  • Cancer Biology
  • Molecular Biology

Background:

  • Immune checkpoints regulate immune homeostasis, balancing activation and tolerance.
  • Tumors hijack checkpoint pathways to suppress anti-tumor immunity and promote cancer progression.
  • Current immunotherapies targeting PDL1-PD1, CTLA4, and LAG3 show limited efficacy due to checkpoint dysregulation.

Purpose of the Study:

  • To investigate the multilayered regulatory mechanisms controlling immune checkpoint abundance and function.
  • To connect these regulatory processes to tumor immune evasion and therapeutic resistance.
  • To inform biomarker development and mechanism-guided strategies for enhancing immunotherapy.

Main Methods:

  • Analysis of genetic, epigenetic, transcriptional, post-transcriptional, translational, and post-translational regulation of immune checkpoints.
  • Connecting regulatory mechanisms to immune evasion and therapeutic resistance.
  • Review of current knowledge to guide biomarker and therapeutic strategy development.

Main Results:

  • Immune checkpoint molecules are regulated through complex, multilayered mechanisms across multiple biological levels.
  • Dysregulation of these checkpoints contributes significantly to tumor immune evasion and resistance to immunotherapy.
  • Understanding these regulatory networks provides insights into potential therapeutic vulnerabilities.

Conclusions:

  • Multilayered regulatory mechanisms critically control immune checkpoint expression and function in cancer.
  • Targeting these regulatory pathways offers opportunities to overcome immune evasion and enhance immunotherapy efficacy.
  • This knowledge is crucial for developing improved biomarkers and novel therapeutic strategies to improve cancer treatment outcomes.

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