The roles of tertiary lymphoid structures in orchestrating immune responses in peripheral organs

Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates that develop in non-lymphoid organs under pathological conditions of chronic inflammation, such as cancer, autoimmune diseases, chronic infections, organ transplantation, and age-related disorders. TLSs produce various cytokines and chemokines, and orchestrate local adaptive immune responses by serving as sites for antigen presentation. TLSs have attracted significant attention because of their multifaceted roles in various diseases. However, the diversity in cellular composition, development, and maturation of TLSs, depending on the disease context and organ, makes it challenging to fully understand their characteristics. Several basic and clinical studies have demonstrated the clinical and pathophysiological roles of TLSs, revealing both their protective and harmful effects. In cancer, TLSs generally activate anticancer immune responses, leading to the suppression of tumor growth. Additionally, they contribute to host defense against pathogens in infectious diseases. Conversely, they can provide a niche for autoantibody production, exacerbating autoimmune diseases and chronic rejection in transplanted organs. In age-related diseases, they may prolong tissue inflammation and hinder tissue repair. The pathophysiological significance of TLSs has prompted the development of therapeutic strategies that target their formation and maturation. However, their potential systemic immunological effects must be carefully considered. Recent advances in single-cell omics technologies have facilitated a deeper understanding of the diverse cellular components of TLSs and their cell-cell interactions, which may contribute to the development of TLS-specific therapies. The fact that TLSs can only be identified using invasive diagnostic methods remains a barrier to further research. Advances in artificial intelligence-driven pathology diagnostics and improvements in imaging technologies for noninvasive detection are expected to accelerate TLS research. Categorizing various conditions with TLSs as 'TLS-related diseases' could deepen our understanding of TLS pathophysiology and lead to the development of novel therapeutic strategies.