Lymphoid structures (LS) arising in nonlymphoid tissues are increasingly recognized as active immune niches rather than simple consequences of chronic inflammation. In this review, we propose a framework that distinguishes inflammatory lymphoid structures (ILS) from mature tertiary lymphoid structures (mTLS), while acknowledging that these entities may form a continuum in some settings and represent distinct inflammatory states in others. We discuss how LS develop across autoimmunity, cancer, transplantation, immune-related adverse events, and aging, and how differences in architecture, stromal organization, antigen persistence, and tolerance checkpoints shape their biological outputs. Whereas mTLS are typically associated with follicular organization, germinal center-like reactions, and local clonal diversification, ILS may instead sustain inflammation through extrafollicular activation, survival niche formation, and tissue-adapted immune specialization. Importantly, the functional impact of LS is highly context dependent: they may promote pathogenic autoreactivity in autoimmune disease, support protective antitumor immunity in cancer, or acquire regulatory or suppressive features depending on the microenvironment. We also review current therapeutic strategies targeting LS and discuss how spatial transcriptomics and artificial intelligence may refine their detection, classification, and functional interpretation. Altogether, this perspective supports viewing LS as heterogeneous tissue immune niches rather than a binary TLS category, with major implications for pathogenesis, biomarker development, and therapeutic intervention.
Frutoso et al. (Fri,) studied this question.