Proteome profiles of esophageal squamous cell carcinoma tie mitochondrial complex I to immunotherapy
Immunotherapy has revolutionized cancer treatment, yet many patients show non-sensitivity. Here, we collected treatment-naïve samples from 190 esophageal squamous cell carcinoma (ESCC) patients undergoing anti-programmed death 1 (PD1) immunotherapy for proteome, phosphoproteome, and immunohistochemistry (IHC) analysis. Proteome-based stratification of ESCC identifies three proteomic subtypes (G-I-G-III) related to immunotherapy response and different molecular features, revealing that patients with high mitochondrial complex I protein expression show sensitivity to anti-PD1 immunotherapy. High mitochondrial complex I protein expression of ESCC cells or patient-derived organoids increases sensitivity to CD8 + T cell-mediated killing in the co-culture systems. Phosphoproteomic data analysis reveals YAP1 activation impairs immunotherapy efficacy. Inhibiting YAP1 or increasing mitochondrial complex I levels bolsters immunotherapy effectiveness in ESCC allograft tumors. Finally, we develop a highly accurate predictive model (AUC ≥ 0.90) by the signatures of mitochondrial complex I-mediated anti-tumor immune response and validate it in independent cohorts. This study provides a rich resource for investigating the mechanisms and indicators of immunotherapy in ESCC.
Authors
- Yan Li (ORCID: https://orcid.org/0000-0001-9041-7675)
- Kai Li (ORCID: https://orcid.org/0000-0003-4898-2827)
- Changsheng Du (ORCID: https://orcid.org/0000-0002-7922-9785)
- Guichao Li (ORCID: https://orcid.org/0000-0003-4911-5995)
- Sha Tian (ORCID: https://orcid.org/0000-0003-4407-8873)
- Zhanxian Shang (ORCID: https://orcid.org/0000-0003-4732-5104)
- Chan Xiang (ORCID: https://orcid.org/0000-0003-1819-1645)
- Fahan Ma (ORCID: https://orcid.org/0000-0002-3474-1179)
- Su-Bei Tan
- Chen Ding (ORCID: https://orcid.org/0000-0001-8673-3464)
- Jiaying Deng
- Haohua Teng
- Yan Pu
- Zhaoyu Qin
- Jie Lv
- Bing Wang
- Yuchen Han
- Yunzhi Wang
- Chao Zhang
- Mingqiang Kang
- Weiguang Zhang
- Jinzhi Wei
- Peipei Zhang
- Jinwen Feng
Institutions
- Tongji University (CN)
- Fujian Medical University (CN)
- Shanghai Medical College of Fudan University (CN)
- University of Electronic Science and Technology of China (CN)
- Shanghai Jiao Tong University (CN)
- Fudan University (CN)
- Shanghai Chest Hospital (CN)
- Fudan University Shanghai Cancer Center (CN)
- Pudong Medical Center (CN)
- Shanghai Clinical Research Center (CN)
- Tongji Hospital (CN)
- Union Hospital (CN)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2026-04-11
- DOI
- https://doi.org/10.1038/s44321-026-00413-9
- Primary Topic
- Hippo pathway signaling and YAP/TAZ
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- Science and Technology Commission of Shanghai Municipality
- National Key Research and Development Program of China
- Program of Shanghai Academic Research Leader