Tertiary lymphoid structures in breast cancer: Mechanistic insights, subtype-specific patterns, and therapeutic implications.

Abstract

Breast cancer exhibits substantial molecular and immunological heterogeneity, with tertiary lymphoid structures (TLSs) emerging as key modulators of local antitumor immunity. TLSs display subtype-specific prevalence and maturity, with mature TLSs enriched in triple-negative (TNBC) and human epidermal growth factor receptor 2-positive (HER2+) tumors, correlating with improved prognosis, response to neoadjuvant therapy, and sensitivity to immune checkpoint inhibitors, whereas hormone receptor-positive (HR+) tumors often lack organized TLSs and show limited immunogenicity. TLS formation is orchestrated by cytokine-chemokine networks, lymphoid tissue organizer/inducer interactions, and vascular remodeling via high endothelial venules, yet the regulatory mechanisms and functional heterogeneity across subtypes remain incompletely understood. Detection strategies range from histopathology and multiplex immunohistochemistry to spatial transcriptomics and radiomics, but standardization, reproducibility, and clinical scalability remain major hurdles. Emerging interventions-including chemotherapy, immune checkpoint blockade, chemokine delivery, and combinatorial strategies-can induce or mature TLSs, offering potential therapeutic leverage, yet safety, phenotypic fidelity, and context-dependent efficacy require careful evaluation. Collectively, TLSs represent a dynamic, therapeutically targetable component of the tumor microenvironment; however, translating TLS biology into precision immuno-oncology demands mechanistic insight, standardized assessment, and integration with spatial multi-omic frameworks to inform subtype-specific, clinically actionable strategies.