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<p>Protein Tyrosine Phosphatase 1B (PTP1B) is a key immune regulator in cancer and an attractive immunotherapy target, yet progress is limited by the lack of selective inhibitors. Here, we identify Fumosorinone (FU), a natural product from <i>Isaria fumosorosea</i>, as a potent and selective allosteric inhibitor of PTP1B. In a murine colon tumor model, FU enhances anti-tumor immunity by reshaping the microenvironment, strengthening CD8⁺ T-cell responses, and promoting M1-like macrophage polarization. Enzymatic and biophysical analyses confirm its potency and direct engagement with PTP1B. A co-crystal structure defines a previously uncharacterized allosteric pocket that stabilizes the inactive state of the enzyme. This pocket is poorly conserved across the PTP family, consistent with minimal activity toward related phosphatases except TCPTP. Guided by this insight, virtual screening identifies additional inhibitors. These findings provide a structural basis for selective PTP1B targeting and support future immunotherapy development and rational drug discovery efforts.</p>

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Structural basis of Fumosorinone-mediated allosteric inhibition of PTP1B for cancer immunotherapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月28日

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  • Jun Zhang,
  • Lianyun Lin,
  • Nanxin Gong,
  • Weikang Li,
  • Yu Liu,
  • Rajamanikandan Sundarraj,
  • Yilong Li,
  • Meijing Dong,
  • Junan Ma,
  • Kenneth Woycechowsky,
  • Kunrong Mei,
  • Yang Ge,
  • Zhiguang Yuchi,
  • Duqiang Luo

摘要

Protein Tyrosine Phosphatase 1B (PTP1B) is a key immune regulator in cancer and an attractive immunotherapy target, yet progress is limited by the lack of selective inhibitors. Here, we identify Fumosorinone (FU), a natural product from Isaria fumosorosea, as a potent and selective allosteric inhibitor of PTP1B. In a murine colon tumor model, FU enhances anti-tumor immunity by reshaping the microenvironment, strengthening CD8⁺ T-cell responses, and promoting M1-like macrophage polarization. Enzymatic and biophysical analyses confirm its potency and direct engagement with PTP1B. A co-crystal structure defines a previously uncharacterized allosteric pocket that stabilizes the inactive state of the enzyme. This pocket is poorly conserved across the PTP family, consistent with minimal activity toward related phosphatases except TCPTP. Guided by this insight, virtual screening identifies additional inhibitors. These findings provide a structural basis for selective PTP1B targeting and support future immunotherapy development and rational drug discovery efforts.