Tertiary lymphoid structures in pancreatic cancer: molecular mechanisms, heterogeneity, and clinical significance

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal solid tumors and is largely refractory to current immunotherapy. Tertiary lymphoid structures (TLS), ectopic immune cell aggregates within the tumor microenvironment, have emerged as candidate biomarkers and therapeutic targets in this setting. This review synthesizes current evidence on TLS biology in PDAC, focusing on three interrelated themes: the cascade through which TLS form, the multidimensional heterogeneity that determines their function, and the clinical implications of these features. TLS formation in PDAC proceeds through three overlapping phases-stromal fibroblast reprogramming, chemokine-driven immune cell recruitment, and progressive structural maturation-each shaped by the uniquely immunosuppressive PDAC microenvironment. The resulting structures display substantial heterogeneity in cellular composition, maturation state, and spatial distribution. Mature, germinal-center-containing intratumoral TLS have been most consistently associated with improved survival and with response to chemotherapy and immunotherapy, whereas immature peritumoral TLS may be associated with adverse outcomes in specific clinical contexts, particularly after neoadjuvant chemotherapy. Several PDAC-associated features-including an "all-or-none" distribution pattern, generally low maturation rates, the gut-pancreas IL-33/ILC2 axis, and divergent cancer-associated fibroblast programs-may distinguish PDAC TLS from those of more immunogenic malignancies. The relative contributions of extrafollicular and canonical germinal-center B-cell responses in human PDAC remain unresolved. Translating these observations into clinical benefit will require harmonized TLS definitions, tissue-sampling rules, maturation-marker panels, scoring methods, and clinically relevant endpoints, followed by prospective feasibility and reproducibility testing in well-annotated institutional cohorts. Multicenter external validation should follow only after feasibility and reproducibility are established.