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Updated: Jun 22, 2025

Identifying PD-1/PD-L1 Inhibitors with Surface Plasmon Resonance Technology
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Published on: May 2, 2025

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A combination of protein phosphatase 2A inhibition and checkpoint immunotherapy: a perfect storm

Mary C Clark1,2, Rongze Olivia Lu3,4, Winson S Ho3

  • 1Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA, USA.

Molecular Oncology
|June 27, 2024
PubMed

Insights

Inhibiting protein phosphatase 2A (PP2A) may enhance cancer immunotherapy by increasing tumor antigen expression and T-cell activity. This approach shows promise for improving responses to immune checkpoint blockade therapies.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Immune checkpoint blockade (ICB) is a powerful cancer therapy, but limited patient response necessitates combination strategies.
  • Protein phosphatase 2A (PP2A) plays a critical role in cellular signaling pathways relevant to cancer immunity.

Purpose of the Study:

  • To investigate the potential of inhibiting PP2A to enhance the efficacy of ICB and other T-cell-mediated cancer therapies.
  • To explore the mechanisms by which PP2A inhibition impacts anti-tumor immunity.

Main Methods:

  • Preclinical cancer models were utilized to assess the effects of PP2A inhibition.
  • Analysis of molecular pathways including neoantigen expression and the cGAS/STING pathway.
  • Evaluation of T-cell responses, including regulatory T-cell suppression and cytotoxic T-cell activation.

Main Results:

  • PP2A inhibition was found to increase tumor neoantigen expression and activate the cGAS/STING pathway.
  • Suppression of regulatory T-cells and enhanced cytotoxic T-cell activation were observed.
  • In preclinical studies, PP2A inhibition synergized with ICB, and patient data suggested improved ICB response in tumors with PP2A mutations.

Conclusions:

  • Inhibition of PP2A represents a promising strategy to sensitize tumors to ICB and T-cell-based therapies.
  • Targeting PP2A may overcome resistance mechanisms and broaden the patient population benefiting from current immunotherapies.
Keywords:
PP2ATIL therapycheckpoint inhibitor

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