PTPN2 inhibition unleashes response to STING agonism in head and neck squamous cell cancer
cGAS-STING signaling can promote antitumor immunity, and tumor cell STING is suppressed in a variety of cancer subtypes that resist immune checkpoint blockade. Although STING agonists have failed clinical trials, precision approaches targeting restoration of tumor cell STING expression have yet to be explored. Here, we report that head and neck squamous cell cancer (HNSCC) exhibits a mechanism of STING suppression related to upregulation of protein tyrosine phosphatase non-receptor (PTPN) type 2 (PTPN2) that is also evident in other cancers. PTPN2 inhibition (PTPN2i) increases HNSCC tumor cell STING by restoring IFNγ-STAT1-mediated induction of STING mRNA. This restores sensitivity to STING agonism and natural killer cell activation, suppressing tumor growth in an immune cell-dependent manner in anti-PD-1 refractory syngeneic HNSCC mouse tumor models in female mice. Together, these findings demonstrate that PTPN2i can unleash STING agonist response, providing a rationale for the evaluation of this therapeutic combination in HNSCC and potentially other cancer types.
Authors
- Cong Fu (ORCID: https://orcid.org/0009-0009-2204-6441)
- Patrick C. Gedeon
- Caroline G. Fahey (ORCID: https://orcid.org/0000-0003-4155-5662)
- Yaiza Senent (ORCID: https://orcid.org/0000-0002-0352-901X)
- Ann Marie Egloff (ORCID: https://orcid.org/0000-0002-1182-2793)
- Marco Campisi (ORCID: https://orcid.org/0000-0002-9288-5285)
- Benjamin K. Eschle
- Michihisa Kono (ORCID: https://orcid.org/0000-0002-8506-928X)
- Kenneth Ngo (ORCID: https://orcid.org/0000-0001-5511-2825)
- Cun Lan Chuong
- Kartik Sehgal (ORCID: https://orcid.org/0000-0003-4391-6943)
- Cloud Peter Paweletz (ORCID: https://orcid.org/0000-0002-2287-5663)
- Tran C. Thai (ORCID: https://orcid.org/0000-0003-4799-0876)
- Koji Haratani (ORCID: https://orcid.org/0000-0002-1767-6854)
- Prafulla C. Gokhale (ORCID: https://orcid.org/0000-0002-1974-5921)
- Navin R. Mahadevan (ORCID: https://orcid.org/0000-0002-6805-8861)
- John D. Quadarella
- Chayapatou Chayawatto
- Robert T. Manguso
- Maia Shea Lineberry
- David A Barbie
- Ravindra Uppaluri
- Jonathan D Schoenfeld
- Omar Avila Monge
- Elena V Ivanova
- Zehua Li
Institutions
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- University of Michigan (US)
- Parker Institute for Cancer Immunotherapy (US)
- Dana-Farber Cancer Institute (US)
- Dana-Farber/Harvard Cancer Center (US)
- Center for Cancer Research (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-05-02
- DOI
- https://doi.org/10.1038/s41467-026-72372-1
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Cancer Institute