Abstract
Tertiary lymphoid structures (TLSs) arise in non-lymphoid tissues in response to persistent antigen stimulation and chronic inflammation. Spanning organs from lung and liver to meninges, skin, and beyond, TLSs range from loose aggregates of immune cells to fully mature structures containing functional germinal centers (GC). In this review, we provide a comprehensive overview of TLS formation, architecture, and function across diverse tissues, highlighting both shared features and tissue-specific adaptations. We then explore the clinical relevance of TLS in infections, autoimmunity, cancer, and allergy, emphasizing their dual roles in mediating protective immunity and driving pathology. Finally, we discuss emerging technologies that are transforming our ability to dissect TLSs at high resolution (including spatial multi-omics, advanced imaging, and digital pathology), enabling mechanism-guided strategies to modulate TLSs therapeutically. Framing TLSs through the lens of maturation and tissue context provides a foundation for interpreting their clinical associations and for enhancing or dismantling these niches according to need.