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

  • Commun Biol. 2026 May 28;9(1):729. doi: 10.1038/s42003-026-10329-2.
Jun Zhang  #  1  2  3 ,  Lianyun Lin  #  3  4 ,  Nanxin Gong  1  5 ,  Weikang Li  1 ,  Yu Liu  1 ,  Rajamanikandan Sundarraj  2  3 ,  Yilong Li  2  3 ,  Meijing Dong  6 ,  Junan Ma  7 ,  Kenneth Woycechowsky  8 ,  Kunrong Mei  3 ,  Yang Ge  9 ,  Zhiguang Yuchi  10  11 ,  Duqiang Luo  12
Affiliations
  • 1. College of Life Sciences, Institute of Life Science and Green Development and Hebei Innovation Center for Bioengineering and Biotechnology, Hebei University, Baoding, China.
  • 2. State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin, China.
  • 3. State Key Laboratory of Synthetic Biology and Frontiers Science Center for Synthetic Biology, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, China.
  • 4. College of Bee Science and Biomedicine, Fujian Agriculture and Forestry University, Fuzhou, Fujian, China.
  • 5. State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and College of Pharmacy, Nankai University, Tianjin, China.
  • 6. Department of Bioinformatics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
  • 7. Department of Chemistry, State Key Laboratory of Synthetic Biology, Tianjin University, Tianjin, China.
  • 8. School of Molecular Sciences, Arizona State University, Tempe, AZ, USA.
  • 9. State Key Laboratory of Synthetic Biology and Frontiers Science Center for Synthetic Biology, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, China. [email protected].
  • 10. State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin, China. [email protected].
  • 11. State Key Laboratory of Synthetic Biology and Frontiers Science Center for Synthetic Biology, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, China. [email protected].
  • 12. College of Life Sciences, Institute of Life Science and Green Development and Hebei Innovation Center for Bioengineering and Biotechnology, Hebei University, Baoding, China. [email protected].
  • # Contributed equally.
PMID: 42209755 DOI: 10.1038/s42003-026-10329-2
Abstract

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.

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