Tertiary lymphoid structures in gastrointestinal cancer: orchestrating tumour microenvironmental immune subcycles to elegantly amplify the cancer immunity cycle.

INTRODUCTION: Gastrointestinal (GI) cancers remain a major global health burden, with high incidence and mortality despite advances in multimodal therapies. Tertiary lymphoid structures (TLSs), ectopic lymphoid aggregates within the tumour microenvironment (TME), have emerged as key regulators of antitumour immunity and potential predictors of immunotherapy response. However, a focused synthesis of TLS biology specific to GI malignancies is still lacking.

METHODS: We conducted a comprehensive narrative review of current literature to summarize the formation, maturation and functional roles of TLSs, with particular emphasis on their immunological and clinical relevance in GI cancers.

RESULTS: TLSs structurally resemble secondary lymphoid organs and function as localized hubs for antigen presentation, lymphocyte recruitment and adaptive immune activation. In GI tumours, TLS presence, density and maturation status are closely associated with enhanced immune infiltration, improved prognosis and better response to immune checkpoint inhibitors. Emerging evidence also suggests that therapeutic interventions, including chemotherapy, radiotherapy and immunotherapy, may influence TLS formation and function. However, TLS heterogeneity and potential immunosuppressive components present challenges for their clinical application.

CONCLUSIONS: TLSs represent promising biomarkers and therapeutic targets in GI oncology. While strategies to induce or modulate TLSs may enhance antitumour immunity, their clinical translation requires careful consideration of immune-related adverse effects and standardization of assessment methods. Integrating TLS-based approaches may advance precision immunotherapy in GI cancers.