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PTPN1/PTPN2 inhibition improves NK cancer therapy by enhancing IL-2 and mitigating TGFβ1 responses

Chu-Han Feng1,2, Linda Peltier3,4, Tiffanie Chouleur1,5,6

  • 1Rosalind and Morris Goodman Cancer Institute, School of Biomedical Sciences, Faculty of Medicine, McGill University, Montreal, QC, H3A 1A3, Canada.

EMBO Reports
|April 15, 2026
PubMed

Insights

Dual inhibition of protein tyrosine phosphatases PTPN1 and PTPN2 enhances natural killer (NK) cell anti-cancer activity. This approach overcomes tumor microenvironment suppression and improves immunotherapy efficacy.

Area of Science:

  • Immunology
  • Cancer Therapy
  • Cell Biology

Background:

  • Natural killer (NK) cells are crucial for anti-cancer immunotherapy.
  • Tumor microenvironments often suppress NK cell activity, limiting therapeutic efficacy.

Purpose of the Study:

  • To investigate the impact of dual inhibition of protein tyrosine phosphatases PTPN1 and PTPN2 (PTPN1/N2) on NK cell function.
  • To assess the potential of PTPN1/N2 inhibition as a strategy to enhance NK cell-based immunotherapy.

Main Methods:

  • Genetic silencing and pharmacological dual inhibition of PTPN1/N2 in NK cells.
  • In vitro and in vivo assays to measure NK cell cytolytic activity.
  • Analysis of NK cell activation markers, effector molecules, and signaling pathways (JAK/STAT).
  • Assessment of NK cell resistance to TGFβ-1 immunosuppression.

Main Results:

  • Dual PTPN1/N2 inhibition significantly enhanced NK cell anti-tumor cytolytic activity.
  • Inhibition increased expression of activation markers and effector molecules (granzyme B, IFN-γ).
  • Enhanced NK cell activity demonstrated resistance to TGFβ-1 immunosuppression.
  • Targeting PTPN1/N2 promoted JAK/STAT signaling and IL-2 sensitization.
  • Improved NK cell activity against patient-derived glioblastoma cells.

Conclusions:

  • Dual targeting of PTPN1/N2 represents a promising strategy to enhance NK cell-based immunotherapy.
  • This approach can overcome tumor microenvironment-mediated immunosuppression.
  • PTPN1/N2 inhibition holds potential for improving "off-the-shelf" NK cell therapies.
Keywords:
Anti-cancer ImmunotherapyCytokine SignalingNK CellsPTPN1 (PTP1B)PTPN2 (TC-PTP)

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