Tertiary lymphoid structures in cancer: spatiotemporal heterogeneity, immune orchestration, and translational opportunities

Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates that form in or in close proximity to tumors and other chronically inflamed tissues, where they serve as crucial sites for local antigen presentation, lymphocyte priming, and adaptive immune coordination. Increasing evidence across diverse cancers supports TLSs as key modulators of antitumor immunity, correlating with improved patient prognosis and response to immune checkpoint blockade. Yet, TLSs exhibit striking spatiotemporal and functional heterogeneity-ranging from immune-stimulatory to immune-suppressive-which complicates their clinical interpretation and therapeutic targeting. Recent studies have focused on elucidating the molecular cues driving TLS induction, the mechanisms regulating their maturation, and their dynamic interactions with the tumor microenvironment. In this review, we provide an integrated overview of these advances and discuss the clinical and translational implications of TLSs as prognostic biomarkers and immunotherapeutic targets.