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

Dongshao Chen,Zitong Zhao,Ruoxi Hong,Di Yang,Ying Gong,Qingnan Wu,Yan Wang,Yiren Cao,Jie Chen,Yidi Tai,Haoyu Liu,Jinting Li,Jiawen Fan,Weimin Zhang,Yongmei Song,Q. Zhan

Published 2025 in Nature Communications

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. Necroptosis in cancer cells remains incompletely understood. Here, the authors show that inhibition of FGFR2 could induce necroptosis via crosstalk between the NF2-Hippo-YAP and RIP1-MST1-MLKL pathways and shapes an immunosuppressive tumor microenvironment.

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