Tertiary Lymphoid Structures in Human Melanoma: Molecular Mechanisms and Therapeutic Opportunities

Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates often found in chronic inflammatory conditions, including cancer. These structures, which share many cellular and functional features with secondary lymphoid organs, can profoundly influence the tumor microenvironment by promoting local anti-tumor immune activation. TLSs have been observed in various cancers, including melanoma, and are associated with improved responses to immunotherapy and clinical outcomes. However, our understanding of the molecular mechanisms underlying TLS formation and function remains incomplete. This review summarizes the current findings on TLSs in human melanoma, drawing from multiple studies to provide an updated overview. We discuss the cellular composition, spatial distribution, and genetic signatures of TLSs at different stages of melanoma pathogenesis and in subtypes including acral, uveal, and desmoplastic melanoma. Additionally, we examine the influence of tumor mutational burden (TMB) and complement activation on TLS formation, as well as the role of TLSs in immune checkpoint inhibitor therapy. We also highlight the potential of TLSs as indicators for disease progression and treatment response, and review preclinical strategies aimed at inducing TLSs to improve therapeutic outcomes. This synthesis aims to support ongoing research into the role of TLSs in melanoma immunobiology.