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

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.