The Prognostic Significance of Tertiary Lymphoid Structures in Head and Neck Cancers: A Systematic Review and Meta‐Analysis

Background: Head and neck squamous cell carcinoma (HNSCC), particularly oral squamous cell carcinoma (OSCC), is associated with poor survival despite therapeutic advances. Tertiary lymphoid structures (TLSs) are emerging components of the tumor microenvironment, but their prognostic significance in HNSCC remains unclear.

Objective: To systematically review and meta-analyze the prognostic impact of TLSs in HNSCC.

Methods: PubMed/MEDLINE, Scopus, ScienceDirect, and Embase were searched through August 2025. Eligible studies evaluated TLS presence, density, maturity, or spatial distribution in histologically confirmed HNSCC. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using fixed-effects models. Risk of bias and certainty of evidence were assessed using QUIPS and GRADE, respectively.

Results: Seventeen studies involving more than 2309 patients were included. TLS-positive tumors were significantly associated with improved overall and disease-free survival (DFS) (p < 0.001). Absence of TLSs was associated with worse overall survival (HR: 2.20, 95% CI: 1.74-2.78, I² = 26%) and poorer DFS (HR: 2.21, 95% CI: 1.49-3.28, I² = 0%). This adverse prognostic effect persisted in the OSCC subgroup (HR: 1.97, 95% CI: 1.42-2.73, I² = 28%). Beyond quantitative presence, TLS maturation and spatial distribution influenced prognosis, with mature intratumoral TLSs associated with more favorable outcomes. Moreover, emerging evidence suggests that TLSs may also predict response to immunotherapy, particularly immune checkpoint blockade.

Conclusion: TLSs are strong prognostic biomarkers in HNSCC. Their presence, maturity, and spatial context significantly influence survival, supporting their role in prognostic stratification and future therapeutic strategies. TLS maturity emerges as a promising feature for standardized scoring systems and should be further explored in future studies.