Targeting SERPINB3–MAPK axis-mediated cuproptosis resistance enhances the response to antitumor immunotherapy
Xiaoxiao Huang, Cheng-Ke Xie, Y. L. Mo, Wěi Li, Yongding Wu, Zhi-Yuan Li, Haoxiang Zhang, Ge Li, Long Jin, Xin-Quan Lin, Jian-Fei Hu, Yinhao Chen, Hong-Yi Lin, Shun‐Cang Zhu, Jun Lü, Hou-Juan Zhu, Wanwan Wang, Yi Huang, Zu-Wei Wang, Long Huang, Danfeng Wang, Yi-Feng Tian, Cheng‐Yu Liao, Shi Chen
Abstract
Cuproptosis, a newly identified form of cell death, is closely linked to copper homeostasis and protein lipoylation. Using a multi-omics approach, we firstly reveal that SERPINB3 confers cuproptosis resistance in pancreatic cancer and functions as a theranostic biomarker. Mechanistically, SERPINB3 inhibits FDX1 transcription by activating the MAPK signaling pathway, thereby conferring cuproptosis resistance. We further demonstrated that SERPINB3 directly interacts with MEK1, impeding its chaperone-mediated autophagic degradation, which ultimately leads to sustained activation of the MAPK signaling pathway. Additionally, we found that SERPINB3 promotes pancreatic cancer immune evasion by upregulating PD-L1 expression on tumor cells. This phenomenon motivated the development of a triple-combination strategy consisting of MAPK inhibition, cuproptosis induction, and αPD-1 therapy for pancreatic cancer patients with high SERPINB3 expression. To this end, we further developed a metal-organic framework (MOF) loaded with both copper ions and MEK inhibitor, which significantly triggers tumor-specific cuproptosis and enhances antitumor immunity. In summary, SERPINB3 serves as a predictive biomarker to inform therapeutic strategies targeting cuproptosis, thereby establishing a novel paradigm for cancer immunotherapy that integrates metal biology, targeted therapy, and immune modulation.