The Emerging Role of Tertiary Lymphoid Structures as Predictive and Prognostic Biomarkers of Immunotherapy in Cancer

ABSTRACT Background Immune checkpoint inhibitors (ICIs) have improved outcomes across several cancers, yet many patients do not respond, highlighting the need for robust predictive biomarkers. Tertiary lymphoid structures (TLS), ectopic lymphoid aggregates that support local antigen presentation and adaptive immune activation, have emerged as potential indicators of favourable prognosis and immunotherapy responsiveness. Methods This review summarises current clinical and translational evidence examining the prognostic and predictive value of TLS in solid malignancies. Studies assessing TLS presence, organisation, and biological function were identified through searches of major scientific databases and evaluated with respect to their association with patient outcomes and responses to ICIs. Results Across multiple tumour types, TLS correlate with improved survival and enhanced anti‑tumour immune activity. TLS‑rich tumours typically show increased infiltration of effector immune cells and more inflamed tumour microenvironments. Several studies also indicate that TLS maturity, particularly the presence of germinal‑centre‑like features, strengthens their predictive value for ICI benefit. However, substantial variation exists in TLS assessment methods and definitions, limiting comparability and hindering translation into routine clinical use. Conclusions TLS represent a promising biomarker for prognosis and immunotherapy response. Standardised evaluation methods and prospective clinical validation are essential to enable their integration into personalised treatment strategies.