Targeting SERPINB3–MAPK axis-mediated cuproptosis resistance enhances the response to antitumor immunotherapy
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.
Authors
- Cheng‐Yu Liao (ORCID: https://orcid.org/0000-0001-7221-7522)
- Yi-Feng Tian
- Yinhao Chen (ORCID: https://orcid.org/0000-0002-0324-4700)
- Yi Huang (ORCID: https://orcid.org/0000-0001-7273-8301)
- Jun Lü (ORCID: https://orcid.org/0000-0002-9141-6786)
- Y. L. Mo (ORCID: https://orcid.org/0000-0001-5705-7356)
- Long Jin (ORCID: https://orcid.org/0000-0002-6055-4692)
- Hongda Zhu (ORCID: https://orcid.org/0000-0002-3871-8857)
- Wanwan Wang (ORCID: https://orcid.org/0000-0002-0981-1382)
- Wěi Li (ORCID: https://orcid.org/0000-0002-9522-4474)
- Shi Chen (ORCID: https://orcid.org/0000-0002-8207-7479)
- Shun‐Cang Zhu (ORCID: https://orcid.org/0000-0002-6975-3583)
- Xiaoyan Lin
- Haoxiang Zhang (ORCID: https://orcid.org/0000-0002-6302-0901)
- Danfeng Wang (ORCID: https://orcid.org/0009-0002-2059-3168)
- Jian-Fei Hu (ORCID: https://orcid.org/0009-0002-0595-0518)
- Yongding Wu (ORCID: https://orcid.org/0009-0000-4874-2589)
- Zuwei Wang (ORCID: https://orcid.org/0000-0002-2568-9364)
- Zhi-Yuan Li (ORCID: https://orcid.org/0009-0007-9619-6317)
- Hong-Yi Lin (ORCID: https://orcid.org/0000-0002-4623-0819)
- Long Huang (ORCID: https://orcid.org/0000-0003-1339-9906)
- Xiaoxiao Huang (ORCID: https://orcid.org/0000-0003-1083-2217)
- Cheng-Ke Xie (ORCID: https://orcid.org/0000-0002-7986-7226)
- Ge Li (ORCID: https://orcid.org/0009-0002-3650-5791)
Institutions
- Fujian Medical University (CN)
- Ningbo No. 2 Hospital (CN)
- Mengchao Hepatobiliary Hospital (CN)
- Institute of Materials Research and Engineering (SG)
- Fujian Provincial Hospital (CN)
- Gaozhou People's Hospital (CN)
Publication Details
- Journal
- Molecular Cancer
- Published
- 2025-11-22
- DOI
- https://doi.org/10.1186/s12943-025-02529-x
- Citations
- 1
- Primary Topic
- Ferroptosis and cancer prognosis
- Type
- article
- Field-Weighted Citation Impact
- 1.52