Clinical impact and therapeutic potential of tertiary lymphoid structures in melanoma

Tertiary lymphoid structures (TLS) are ectopic lymphoid aggregates that arise in nonlymphoid tissues under conditions of chronic inflammation, including cancer. Structurally and functionally resembling secondary lymphoid organs, TLS consist of organized T-cell zones, B-cell follicles, dendritic cells, high endothelial venules, and specialized stromal cells, enabling local antigen presentation and adaptive immune activation. In melanoma, the prototypical immunogenic tumor, the presence of TLS within the tumor microenvironment has been associated with enhanced immune surveillance and favorable clinical outcomes. However, emerging evidence indicates that TLS can also harbor immunosuppressive niches, potentially depending on their developmental stage and cellular composition. In this review, we summarize the molecular and cellular mechanisms underlying TLS biogenesis and outline the experimental methodologies currently used for their identification and characterization, with a focus on melanoma. We examine the clinical relevance of TLS in both primary and metastatic melanomas and discuss strategies aimed at inducing functional TLS within tumors. By promoting TLS formation to amplify intratumoral immune responses, these approaches hold promise for overcoming resistance to immunotherapy and improving outcomes in advanced melanoma and other malignancies.