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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月2日

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  • Zehua Li,
  • Cong Fu,
  • Kartik Sehgal,
  • Ann Marie Egloff,
  • Tran C. Thai,
  • Omar Avila Monge,
  • Cun Lan Chuong,
  • Yaiza Senent,
  • Maia Shea Lineberry,
  • Benjamin K. Eschle,
  • Koji Haratani,
  • Elena V. Ivanova,
  • Marco Campisi,
  • Navin R. Mahadevan,
  • John D. Quadarella,
  • Patrick C. Gedeon,
  • Jonathan D. Schoenfeld,
  • Michihisa Kono,
  • Caroline G. Fahey,
  • Chayapatou Chayawatto,
  • Kenneth Ngo,
  • Cloud P. Paweletz,
  • Prafulla C. Gokhale,
  • Robert T. Manguso,
  • Ravindra Uppaluri,
  • David A. Barbie

摘要

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.