Targeting senescent EGR1+ B cells enhances immunotherapy efficacy in esophageal squamous cell carcinoma

  • Cell Rep Med. 2026 Jan 20;7(1):102532. doi: 10.1016/j.xcrm.2025.102532.
Pingjing Zhou  1 ,  Yuchen Zhang  1 ,  Hongyu Zhang  1 ,  Pengyuan Zhao  2 ,  Yifan Guo  1 ,  Guangyin Zhao  3 ,  Yiwei Chu  4 ,  Di Ge  5 ,  Ronghua Liu  6 ,  Jie Gu  7
Affiliations
  • 1. Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
  • 2. Fifth People's Hospital and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
  • 3. Department of Thoracic Surgery, Shanghai Geriatric Medical Center, Zhongshan Hospital, Fudan University, Minhang Meilong, Shanghai 201100, China.
  • 4. Department of Immunology, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
  • 5. Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China. Electronic address: [email protected].
  • 6. Fifth People's Hospital and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China. Electronic address: [email protected].
  • 7. Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China. Electronic address: [email protected].
PMID: 41483805 DOI: 10.1016/j.xcrm.2025.102532
Abstract

The mechanisms for failure of neoadjuvant immune checkpoint blockade (NICB), an established therapy for patients with esophageal squamous cell carcinoma (ESCC), remain unclear. We integrated single-cell RNA data from patients with ESCC pre- and post-NICB, identifying a subset of senescent EGR1-expressing B cells that correlate with poor pathological responses. EGR1 was a key transcription factor regulating B cell senescence. EGR1+ B cells emerged as predictors of adverse outcomes in multiple cohorts. These senescent B cells, through senescence-associated secretory phenotype (SASP), drive chronic inflammation in the tumor microenvironment (TME), promoting the inducement of immunosuppressive TREM2+ tumor-associated macrophages (TAMs), thereby suppressing anti-tumor immunity and contributing to NICB failure. Furthermore, fisetin was identified as an anti-senescence drug for mitigating B cell senescence and enhancing NICB efficacy. Our findings highlight the role of senescent EGR1+ B cells in ESCC immunotherapy failure and suggest targeting B cell senescence as a strategy to improve NICB outcomes.

Keywords
EGR1; TREM2(+) tumor-associated macrophages; cellular senescence; esophageal squamous cell carcinoma; immune checkpoint blockade; senescence-associated secretory phenotype; single-cell RNA sequencing; tumor-infiltrating B cells.
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