Proteome profiles of esophageal squamous cell carcinoma tie mitochondrial complex I to immunotherapy

Fahan Ma; Yan Li; Chan Xiang; Bing Wang; Jie Lv; Zhanxian Shang; Weiguang Zhang; Zhaoyu Qin; Yan Pu; Kai Li; Jinzhi Wei; Su-Bei Tan; Jinwen Feng; Haohua Teng; Peipei Zhang; Jiaying Deng; Yunzhi Wang; Chao Zhang; Sha Tian; Guichao Li; Mingqiang Kang; Changsheng Du; Yuchen Han; Chen Ding

doi:10.1038/s44321-026-00413-9

Proteome profiles of esophageal squamous cell carcinoma tie mitochondrial complex I to immunotherapy

EMBO Mol Med. 2026 Apr 11. doi: 10.1038/s44321-026-00413-9. Online ahead of print.

Authors

Fahan Ma^#¹, Yan Li^#², Chan Xiang^#³, Bing Wang^#¹, Jie Lv^#⁴, Zhanxian Shang^#³, Weiguang Zhang^#⁵, Zhaoyu Qin¹, Yan Pu¹, Kai Li¹, Jinzhi Wei³, Su-Bei Tan¹, Jinwen Feng¹, Haohua Teng³, Peipei Zhang⁵, Jiaying Deng^{6

7

8}, Yunzhi Wang¹, Chao Zhang^{6

7}, Sha Tian¹, Guichao Li^{6

7}, Mingqiang Kang⁹, Changsheng Du¹⁰, Yuchen Han¹¹, Chen Ding¹²

Affiliations

¹ Clinical Research Center for Cell-based Immunotherapy of Shanghai Pudong Hospital, Fudan University Pudong Medical Center, State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai, China.
² Department of Laboratory Medicine, Institute of Laboratory Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
³ Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁴ Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.
⁵ Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, China.
⁶ Department of Radiation Oncology, Departments of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, China.
⁷ Department of Oncology, Institute of Thoracic Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
⁸ Shanghai Clinical Research Center for Radiation Oncology, Shanghai Key Laboratory of Radiation Oncology, Shanghai, China.
⁹ Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, China. 9199115045@fjmu.edu.cn.
¹⁰ Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China. duchangsheng@tongji.edu.cn.
¹¹ Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. ychan@cmu.edu.cn.
¹² Clinical Research Center for Cell-based Immunotherapy of Shanghai Pudong Hospital, Fudan University Pudong Medical Center, State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai, China. chend@fudan.edu.cn.

^# Contributed equally.

PMID: 41965870
DOI: 10.1038/s44321-026-00413-9

Abstract

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.

Abstract

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