Chen Dongshao, Zhao Zitong, Hong Ruoxi, Yang Di, Gong Ying, Wu Qingnan, Wang Yan, Cao Yiren, Chen Jie, Tai Yidi, Liu Haoyu, Li Jinting, Fan Jiawen, Zhang Weimin, Song Yongmei, Zhan Qimin
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.
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.
Nat Commun. 2025 May 3;16(1):4128. doi: 10.1038/s41467-025-59318-9.
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.
癌细胞中坏死性凋亡的多方面作用和机制仍未完全明确。在此，我们证明成纤维细胞生长因子受体2（FGFR2）抑制通过以受体相互作用蛋白1（RIP1）/混合谱系激酶结构域样蛋白（MLKL）依赖的方式诱导坏死性凋亡，从而有效抑制食管鳞状细胞癌（ESCC），并表明RIP3在该途径中是可有可无的。值得注意的是， MST1被确定为坏死性凋亡途径的一个组成部分，它与RIP1和MLKL相互作用，通过在苏氨酸216位点磷酸化MLKL来促进坏死性凋亡。此外，FGFR2抑制诱导丝氨酸518磷酸化并触发泛素介导的神经纤维瘤病2型（NF2）降解，最终导致Hippo信号通路受抑制。随后，Yes相关蛋白（YAP）激活促进RIP1和MLKL转录上调，进一步放大坏死性凋亡。有趣的是，坏死细胞衍生的白细胞介素8（IL-8）刺激外周存活的肿瘤细胞增加程序性死亡受体配体1（PD-LI）表达。FGFR2/PD-L1或FGFR2/IL-8-CXCR1/2的双重阻断在人源化小鼠异种移植模型中强烈阻碍肿瘤生长。总的来说，我们的研究结果描绘了一条依赖于FGFR2-NF2-YAP信号传导的坏死性凋亡替代途径，并揭示了FGFR2的免疫调节作用，为临床癌症治疗中的联合治疗策略提供了有前景的途径。
