Harnessing the FGFR2/NF2/YAP signaling-dependent necroptosis to develop an FGFR2/IL-8 dual blockade therapeutic strategy
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.
Authors
- Yongmei Song (ORCID: https://orcid.org/0000-0002-7789-0158)
- Yiren Cao (ORCID: https://orcid.org/0000-0003-0418-150X)
- Jinting Li (ORCID: https://orcid.org/0000-0001-7469-4728)
- Ruoxi Hong (ORCID: https://orcid.org/0000-0002-2919-1467)
- Dongshao Chen (ORCID: https://orcid.org/0000-0001-5434-0391)
- Yan Wang (ORCID: https://orcid.org/0000-0002-8302-3704)
- Jie Chen (ORCID: https://orcid.org/0000-0002-8800-1539)
- Weimin Zhang (ORCID: https://orcid.org/0000-0002-3348-9813)
- Haoyu Liu (ORCID: https://orcid.org/0000-0002-6741-7295)
- Di Yang (ORCID: https://orcid.org/0000-0001-6359-6794)
- Qimin Zhan (ORCID: https://orcid.org/0000-0002-1731-938X)
- Ying Gong (ORCID: https://orcid.org/0000-0002-4338-3764)
- Zitong Zhao (ORCID: https://orcid.org/0000-0001-9279-0924)
- Yidi Tai
- Qingnan Wu (ORCID: https://orcid.org/0000-0002-1469-941X)
Institutions
- Sun Yat-sen University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Peking University (CN)
- Soochow University (CN)
- National Cancer Center (US)
- Shenzhen Bay Laboratory (CN)
- Peking University Shenzhen Hospital (CN)
- Peking University International Hospital (CN)
- University of Hong Kong - Shenzhen Hospital (CN)
- Sun Yat-sen University Cancer Center (CN)
- Ministry of Education (ET)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-03
- DOI
- https://doi.org/10.1038/s41467-025-59318-9
- Citations
- 6
- Primary Topic
- Hippo pathway signaling and YAP/TAZ
- Type
- article
- Field-Weighted Citation Impact
- 6.91
Funders
- National Natural Science Foundation of China
- Fudan University
- Peking University
- Xiamen University
- Shenzhen Bay Laboratory
- Peking University Health Science Center
- Basic and Applied Basic Research Foundation of Guangdong Province