Multi-omics of tertiary lymphoid structures in breast cancer: clinical significance and biomarker potential

Abstract

Tertiary lymphoid structures (TLSs) are organized immune aggregates that can support local adaptive immune responses within the tumor microenvironment. In breast cancer, particularly triple-negative breast cancer (TNBC), the presence and maturation of TLSs have been associated with prognosis and treatment response; however, heterogeneity in TLS definition, maturation criteria, spatial sampling, and analytical platforms currently limits standardization and routine clinical implementation. Conventional histopathology provides structural information but limited molecular resolution, whereas single-cell RNA sequencing loses the spatial context that is central to TLS organization. High-resolution spatial and multi-omics technologies can partly bridge these gaps by characterizing TLS cellular composition, molecular interactions, and tissue architecture in situ . This review summarizes the biological features, histopathological classification, multi-omics characterization, clinical associations, and emerging therapeutic strategies related to TLSs in breast cancer, with particular attention to methodological limitations and translational barriers. More precise characterization of TLSs may inform future biomarker development and therapeutic strategies in breast cancer. Prospective validation, standardized assessment, and demonstration of incremental clinical utility are required before TLS-based approaches can be incorporated into routine clinical decision-making.