Prognostic value of tertiary lymphoid structures in high-risk esophageal squamous cell carcinoma following neoadjuvant chemoimmunotherapy

BACKGROUND: Tertiary lymphoid structures (TLSs) are implicated in anti-tumor immunity. However, their prognostic value in esophageal squamous cell carcinoma (ESCC) following neoadjuvant chemoimmunotherapy (NCI) remains unestablished, particularly in high-risk subgroups. METHODS: We retrospectively analyzed a cohort of 186 ESCC patients who underwent curative-intent surgery after NCI. TLS density, maturity, and spatial distribution were evaluated. Prognostic models were developed using LASSO and multivariable Cox regression. Spatial proteomic profiling (GeoMx DSP) and immunohistochemistry were performed to characterize TLS-associated immune landscapes in high-risk stage III patients. RESULTS: High overall TLS (oTLS) density and the presence of secondary follicle-like TLSs (SFTs) were independently associated with superior overall survival (OS) and disease-free survival (DFS). Notably, in patients with poor pathological response, lymph node metastasis, or advanced-stage disease, those with robust TLS signatures had survival outcomes that were not significantly different from those of lower-risk patients who lacked favorable TLS features. Furthermore, TLSs in the peritumoral compartment demonstrated significant prognostic value. A TLS-incorporated nomogram and a simplified TLS-based risk-scoring system were developed, which demonstrated superior predictive accuracy over models based on traditional clinicopathological factors alone. Spatial proteomic and immunohistochemical analyses revealed that TLS-high tumors exhibited enrichment of CD38⁺ plasma cells surrounding TLSs. CONCLUSION: TLS characteristics are potent, independent prognostic determinants in ESCC after NCI, capable of mitigating risks associated with adverse clinicopathological features. The developed models provide practical tools for personalized risk stratification, with mechanistic insights linking TLSs to plasma cell-mediated immunity.