Tailoring the Extent of Lymphadenectomy for Esophageal Squamous Cell Carcinoma: Insights From a Comparative Study of Neoadjuvant Chemo‐Immunotherapy and Surgery Cohort

BACKGROUND: Lymph node dissection is crucial for accurate staging and prognosis assessment in esophageal squamous cell carcinoma (ESCC). While sufficient examined lymph nodes (ELNs) are generally linked to better outcomes, how ELN count affects prognosis under immunotherapy remains unclear. METHODS: This study analyzed 621 ESCC patients who underwent R0 resection with or without neoadjuvant chemo-immunotherapy (NACI). Patients were stratified into surgery alone (SA) (n = 451) and NACI (n = 170) groups. Propensity score matching balanced baseline characteristics. The relationship between ELN count and overall survival was analyzed using Cox regression models. Single-cell RNA and T-cell receptor sequencing were performed on paired tumor and lymph node samples to elucidate underlying immune mechanisms. RESULTS: In the NACI cohort, both insufficient (ELN ≤ 23) and excessive (ELN > 31) lymph node resection were independent risk factors for worse overall survival (ELN ≤ 23: HR = 2.29, 95% CI 1.11-4.71, p = 0.024; ELN > 31: HR = 2.71, 95% CI 1.17-6.26, p = 0.020). However, the SA cohort derived continuous survival benefit from higher ELN counts. Single-cell sequencing revealed that NACI enriched a population of activated, tumor-reactive cytotoxic T cells within metastasis-negative lymph nodes. CONCLUSIONS: The optimal ELN count is contingent on treatment strategy. For SA, a more extensive lymphadenectomy improves survival. However, for NACI, a "Goldilocks" principle applies-an ELN count between 24 and 31 balances accurate staging with the preservation of antitumor immunity, advocating for function-preserving, personalized surgery in the immunotherapy era.