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PTPN2 inhibition unleashes response to STING agonism in head and neck squamous cell cancer

Zehua Li1, Cong Fu1, Kartik Sehgal1,2

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Nature Communications
|May 2, 2026
PubMed

Insights

In head and neck cancer, inhibiting PTPN2 restores STING expression, enhancing antitumor immunity. This approach may overcome resistance to current immunotherapies by restoring STING agonist response.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • STING signaling promotes antitumor immunity but is often suppressed in cancers resistant to immune checkpoint blockade.
  • STING agonists have shown limited clinical success, highlighting the need for strategies to restore STING expression.

Purpose of the Study:

  • To investigate mechanisms of STING suppression in head and neck squamous cell cancer (HNSCC).
  • To explore PTPN2 inhibition (PTPN2i) as a strategy to restore STING expression and enhance antitumor immunity in HNSCC.

Main Methods:

  • Analysis of STING suppression mechanisms in HNSCC.
  • Treatment of HNSCC mouse models with PTPN2 inhibitors.
  • Assessment of STING expression, immune cell activation, and tumor growth.

Main Results:

  • HNSCC exhibits STING suppression linked to increased PTPN2.
  • PTPN2i restores STING expression by enhancing IFNγ-STAT1-mediated induction of STING mRNA.
  • PTPN2i restores sensitivity to STING agonism and natural killer cell activation, suppressing tumor growth in anti-PD-1 refractory models.

Conclusions:

  • PTPN2 inhibition can restore STING expression and function in HNSCC.
  • This strategy enhances immune cell-mediated antitumor responses, offering a rationale for combining PTPN2i with STING agonists.
  • The findings suggest potential therapeutic applications for PTPN2i in HNSCC and other cancers.

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