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  3. Harnessing the FGFR2/NF2/YAP signaling-dependent necroptosis to develop an FGFR2/IL-8 dual blockade therapeutic strategy

Harnessing the FGFR2/NF2/YAP signaling-dependent necroptosis to develop an FGFR2/IL-8 dual blockade therapeutic strategy

  • Nat Commun. 2025 May 3;16(1):4128. doi: 10.1038/s41467-025-59318-9.
Dongshao Chen # 1 2,  Zitong Zhao # 3,  Ruoxi Hong # 2,  Di Yang 1,  Ying Gong 1,  Qingnan Wu 1,  Yan Wang 1,  Yiren Cao 1,  Jie Chen 1,  Yidi Tai 1,  Haoyu Liu 1,  Jinting Li 1,  Jiawen Fan 1,  Weimin Zhang 4 5 6,  Yongmei Song 7,  Qimin Zhan 8 9 10 11 12
Affiliations

Affiliations

  • 1 State Key Laboratory of Molecular Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, China.
  • 2 Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China.
  • 3 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 4 State Key Laboratory of Molecular Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, China. zhangweimin@bjmu.edu.cn.
  • 5 Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, China. zhangweimin@bjmu.edu.cn.
  • 6 Department of Oncology, Cancer Institute, Peking University Shenzhen Hospital, Shenzhen Peking University-Hong Kong University of Science and Technology (PKU-HKUST) Medical Center, Shenzhen, China. zhangweimin@bjmu.edu.cn.
  • 7 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. symlh2006@163.com.
  • 8 State Key Laboratory of Molecular Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, China. zhanqimin@bjmu.edu.cn.
  • 9 Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, China. zhanqimin@bjmu.edu.cn.
  • 10 Department of Oncology, Cancer Institute, Peking University Shenzhen Hospital, Shenzhen Peking University-Hong Kong University of Science and Technology (PKU-HKUST) Medical Center, Shenzhen, China. zhanqimin@bjmu.edu.cn.
  • 11 International Cancer Institute, Peking University Health Science Center, Beijing, China. zhanqimin@bjmu.edu.cn.
  • 12 Soochow University Cancer institute, Suzhou, Jiangsu, China. zhanqimin@bjmu.edu.cn.
  • # Contributed equally.
PMID: 40319089 DOI: 10.1038/s41467-025-59318-9
Abstract

The multifaceted roles and mechanisms of Necroptosis in Cancer cells remain incompletely understood. Here, we demonstrate that FGFR2 inhibition potently inhibits esophageal squamous cell carcinoma (ESCC) by inducing Necroptosis in a RIP1/MLKL-dependent manner and show RIP3 is dispensable in this pathway. Notably, MST1 is identified as a necroptotic pathway component that interacts with RIP1 and MLKL to promote Necroptosis by phosphorylating MLKL at Thr216. Additionally, FGFR2 inhibition induces Ser518 phosphorylation and triggers ubiquitin-mediated degradation of NF2, culminating in Hippo pathway suppression. Subsequently, YAP activation promotes RIP1 and MLKL transcriptional upregulation, further amplifying Necroptosis. Intriguingly, IL-8 derived from necrotic cells stimulates peripheral surviving tumor cells to increase PD-L1 expression. Dual blockade of FGFR2/PD-L1 or FGFR2/IL-8-CXCR1/2 robustly impedes tumor growth in humanized mouse xenografts. Collectively, our findings delineate an alternative FGFR2-NF2-YAP signaling-dependent necroptotic pathway and shed light on the immunoregulatory role of FGFR2, offering promising avenues for combinatorial therapeutic strategies in clinical Cancer management.

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