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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月11日

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  • 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

摘要

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.