Prognostic and Spatial Organization of Tertiary Lymphoid Structures in Pancreatic Ductal Adenocarcinoma

Background: Tertiary lymphoid structures (TLSs) may identify immunologically active pancreatic ductal adenocarcinoma (PDAC), but clinical definitions and spatial analyses have been inconsistent. Methods: We integrated a systematic review of 21 studies (22 reports) with patient-aware secondary analyses of seven public molecular datasets. Results: Pathology-defined TLS presence was associated with longer overall survival in five cohorts (1019 patients; random-effects hazard ratio 0.544, 95% confidence interval 0.398–0.743). In pathology-annotated spatial data, a mature-TLS program was enriched in TLS-positive regions at the patient level. B-cell and Tfh/CXCL13 programs showed reproducible positive associations with continuous TLS burden, whereas other program associations were less directionally consistent. An independent spatial cohort supported an rCAF-over-myCAF association with lymphoid probability. Chemokine-axis co-enrichment was observed but did not establish direct signaling. Conclusions: TLSs mark a favorable, spatially organized immune state in PDAC. The evidence supports biomarker and biological hypotheses while retaining boundaries on causality, treatment induction, and clinical prediction.