Role and clinical significance of tertiary lymphoid structures in hepatocellular carcinoma: from prognostic assessment to immunotherapeutic targets

Abstract:

Hepatocellular carcinoma (HCC) is one of the most prevalent primary liver malignancies worldwide and is associated with high mortality. The complex tumor immune microenvironment limits the overall efficacy of current immunotherapies. Recent studies have identified tertiary lymphoid structures (TLS), ectopic lymphoid aggregates formed in chronic inflammatory or tumor tissues, as key regulators of anti-tumor immunity in HCC. Accumulating evidence indicates that the presence, density, maturation status, and spatial distribution of TLS are closely associated with improved survival outcomes, reduced recurrence risk, and enhanced responsiveness to immune checkpoint inhibitors. Moreover, several anti-tumor treatments, including radiotherapy and hepatic arterial infusion chemotherapy, can induce TLS formation or promote their maturation, thereby reshaping the tumor immune microenvironment and strengthening anti-tumor immune responses. This review summarizes the structural characteristics and formation mechanisms of TLS and discusses their prognostic and predictive value in HCC. In addition, potential therapeutic strategies aimed at inducing or targeting TLS and their prospects for clinical translation are highlighted, providing new insights for precision immunotherapy in HCC.