Core Viewpoint - Neoadjuvant immune checkpoint blockade (NICB) therapy has become a first-line treatment for advanced or metastatic esophageal squamous cell carcinoma (ESCC), significantly improving progression-free survival for patients. However, the pathological complete response (pCR) rate is ≤40%, indicating a need to elucidate the mechanisms of resistance to NICB to optimize treatment outcomes [3][7]. Group 1 - A recent study identified a subset of senescent EGR1+ B cells associated with poor pathological responses in ESCC patients undergoing NICB therapy, highlighting the role of these cells in treatment failure [8][11]. - EGR1 is a key transcription factor regulating B cell senescence, and the presence of EGR1+ B cells serves as a predictive marker for poor prognosis across multiple cohorts [8][11]. - The senescent B cells drive chronic inflammation in the tumor microenvironment (TME) through a senescence-associated secretory phenotype (SASP), which induces immunosuppressive TREM2+ tumor-associated macrophages (TAMs), ultimately inhibiting anti-tumor immune responses [8][11]. Group 2 - Fisetin, a natural flavonoid found in various fruits and vegetables, has been shown to alleviate B cell senescence and enhance the efficacy of NICB therapy [10][14]. - The study emphasizes that targeting B cell senescence could be a viable strategy to improve the effectiveness of NICB in treating ESCC [14].