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Updated: Jan 7, 2026

Analysis of Human T Cell Activity in an Allogeneic Co-Culture Setting of Pre-Treated Tumor Cells
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Analysis of Human T Cell Activity in an Allogeneic Co-Culture Setting of Pre-Treated Tumor Cells

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Post-translational modifications of immune checkpoints: molecular mechanisms, tumor microenvironment remodeling, and

Hung-Chia Hsieh1, Lun-Ling Ling1, Yi-Ching Wang2,3

  • 1Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan.

Journal of Biomedical Science
|January 4, 2026
PubMed

Insights

Post-translational modifications (PTMs) dynamically regulate immune checkpoints, influencing cancer immunity and resistance to immune checkpoint blockade (ICB). Targeting these PTMs offers new strategies to enhance antitumor responses and overcome treatment resistance.

Area of Science:

  • Immunology
  • Cancer Biology
  • Biochemistry

Background:

  • Immune checkpoints are crucial for immune regulation and tolerance.
  • Cancer utilizes immune checkpoints to evade antitumor immunity, leading to resistance against immune checkpoint blockade (ICB) therapies.
  • Post-translational modifications (PTMs) are increasingly recognized as key regulators of immune checkpoint function.

Purpose of the Study:

  • To comprehensively review the mechanistic roles of various PTMs in regulating immune checkpoints.
  • To highlight how PTMs influence immune evasion and clinical outcomes in cancer.
  • To explore therapeutic strategies targeting PTMs to overcome ICB resistance.

Main Methods:

  • Literature review of PTMs affecting immune checkpoints like PD-L1, PD-1, TIM-3, TIGIT, CTLA-4, LAG-3, VISTA, BTLA, and SIRPα.
  • Analysis of PTMs' impact on checkpoint stability, trafficking, and function.
  • Examination of PTMs' role in reshaping the tumor microenvironment (TME).

Main Results:

  • PTMs, including phosphorylation, ubiquitination, and glycosylation, critically modulate immune checkpoint activity.
  • These modifications influence immune cell function, antigen presentation, and inflammatory signaling within the TME.
  • Specific PTMs on key checkpoints orchestrate immune evasion and affect patient responses to ICB.

Conclusions:

  • PTMs are central to immune checkpoint regulation and significantly impact cancer immune evasion.
  • Targeting enzymes that regulate PTMs or specific modification sites presents a promising therapeutic avenue.
  • Understanding the PTM landscape is vital for developing novel combination therapies to enhance antitumor immunity and overcome ICB resistance.
Keywords:
Cancer immunotherapyCombination therapyImmune checkpointsPost-translational modificationsTargeted therapyTreatment resistanceTumor microenvironment

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