Tertiary lymphoid structures in breast cancer: formation, immune functions and clinical implications

Tertiary lymphoid structures (TLS) are ectopic lymphoid aggregates that arise in non-lymphoid tissues under chronic inflammatory conditions and during tumor development. Although TLS have often been associated with a favorable prognosis and enhanced therapeutic responsiveness, their biological and clinical significance in breast cancer is highly heterogeneous and cannot be adequately captured by a simple TLS-positive versus TLS-negative classification. In this review, we summarize the structural organization and developmental stages of TLS, with an emphasis on the functional relevance of maturation, including germinal center formation. We further discuss current concepts regarding the mechanisms driving TLS initiation and maturation, including stromal activation, chemokine-guided immune cell recruitment, and high endothelial venule-mediated lymphocyte trafficking. In addition, we examine the major dimensions of TLS heterogeneity in breast cancer, including differences in maturity, spatial location, molecular subtype, and immune cellular composition, and discuss how these variables shape antitumor, immunoregulatory, and context-dependent TLS functions. We also evaluate the current approaches for TLS identification and classification, highlighting the strengths and limitations of histopathology, immunophenotyping, multiplex imaging, and transcriptomic inference. Finally, we discuss the prognostic and predictive relevance of TLS in breast cancer, the barriers limiting its clinical translation, and key priorities for future research. Overall, TLS status represents a promising but context-dependent biomarker and potential therapeutic intermediate whose interpretation requires standardized classification and a deeper mechanistic understanding.