Tertiary lymphoid structures in hepatocellular carcinoma: Prognostic biomarker, immunotherapy predictor, and emerging therapeutic target.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality globally, with many patients presenting with advanced disease that does not respond to standard treatments. While immune checkpoint inhibitors (ICIs) have improved outcomes, their effectiveness is limited in immunologically "cold" tumors, highlighting the urgent need to elucidate the complexity of the tumor immune microenvironment (TIME). Tertiary lymphoid structures (TLSs), ectopic and organized lymphoid aggregates that form at sites of chronic inflammation, have become key players in antitumor immunity. This review thoroughly covers the composition, multistage formation, and functional maturation of TLSs in HCC. We emphasize that the prognostic and predictive value of TLSs depends not only on their presence but also on their spatial localization, structural maturity, and specific immune cell composition. A high density of intratumoral TLSs (iTLSs), especially those with mature germinal centers containing B cells, T follicular helper (Tfh) cells, and dendritic cells (DCs), is strongly linked to better survival and lower recurrence rates. Additionally, TLSs serve as biomarkers for predicting favorable responses to ICIs in both neoadjuvant and adjuvant settings. We also explore how locoregional therapies and specific chemokine axes induce or modulate TLS formation. Finally, we discuss the emerging field of non-invasive TLS evaluation using radiomics and advanced imaging techniques, which promises to guide patient stratification for immunotherapy. TLSs therefore represent promising therapeutic targets with the potential to reprogram the immune milieu of HCC and enable more effective, personalized treatment approaches.