Tertiary lymphoid structures in cancer: their development, composition, clinical prognosis, and the drivers of the anti-tumor responses

Tertiary lymphoid structures (TLS) are ectopic lymphoid aggregates formed under chronic inflammatory tumor microenvironments. Clinical cohorts across solid cancers demonstrate that mature TLS with intact germinal centers serve as independent favorable prognostic biomarkers and predict superior responses to immune checkpoint inhibitors. However, the differences in maturity, spatial localization and cellular composition of TLSs result in heterogeneity in their immunostimulation or immunosuppression, thereby exhibiting dual functions of promoting or anti-tumor. Furthermore, there are significant differences in the maturity assessment methods and definitions of TLS, which jointly hinder the clinical evaluation and targeted treatment of TLSs. In this review, we integrate current understanding of TLS development, molecular drivers, and stromal licensing, and dissect the key mechanisms by which TLS contribute to anti-tumor immunity within tumors. We consolidate standardized TLS detection methods encompassing pathology, multi-omics, and radiogenomics, and further explore the translational value of TLS maturation status, germinal center-like responses, and intratumoral versus peritumoral localization in prognosis and immune checkpoint blockade. We systematically elaborate therapeutic strategies for inducing functional TLS, dissect the intrinsic mechanisms by which TLS synergistically boost the efficacy of adoptive cell therapy and tumor vaccines, and outline major bottlenecks hindering clinical translation. Collectively, this work constructs a comprehensive multi-dimensional framework for TLS research and provides actionable insights to develop TLS-targeted immunotherapies for human cancers.