Dissecting Tertiary Lymphoid Structures in Cancer: Maturation, Localization and Density

Tertiary lymphoid structures (TLSs) refer to ectopic lymphoid aggregates that form in non-lymphoid tissues at sites of chronic inflammation including cancers. TLSs have been recognized as significant predictors of the efficacy of immune checkpoint blockade (ICB) therapies and have the potential to elicit robust anti-tumor immune response. However, recent studies have revealed substantial heterogeneity in TLSs across different individuals and cancer types, which directly impacts the effectiveness of anti-tumor immunity. Concretely, the maturation status, localization, and density of TLSs profoundly influence the dynamic interactions among immune cells within these structures, potentially leading to adverse effects. This review provides an in-depth exploration of how the heterogeneity of TLSs influences cellular composition and immune dynamics, with the objective of influencing the efficacy of ICB therapies and modulating prognostic prediction accuracy. Additionally, the potential of combining TLSs with other biomarkers for predicting anti-tumor immunity outcomes is further investigated, alongside the introduction of advanced technologies for evaluating TLS heterogeneity. Collectively, these analyses aim to advance the understanding of TLS heterogeneity and facilitate its translation into clinical and translational medicine applications.