Intratumoral Tertiary Lymphoid Structures in Hepatocellular Carcinoma: Current Evidence and Future Directions – a Narrative Review

Abstract: Intratumoral tertiary lymphoid structures (iTLSs) have emerged as critical immune features in hepatocellular carcinoma (HCC). This narrative review critically synthesizes current evidence (sourced from PubMed, Embase, and Web of Science up to January 2026) on the biological mechanisms, pathological assessment, non-invasive imaging, and clinical implications of iTLSs. Moving beyond simple binary classifications, we emphasize that precise scoring based on morphological maturation is essential. Clinically, functionally mature iTLSs are strongly associated with favorable prognosis and immunotherapy benefits, though metabolic etiologies (e.g, NASH) can drive complex immunosuppression. Furthermore, while non-invasive radiomic models show high predictive accuracy, their clinical translation is hindered by mathematical overfitting and a “black box” lack of biological interpretability. Translating these biological insights into clinical practice, particularly through non-invasive imaging biomarkers and standardized pathological evaluations, holds great promise for guiding personalized immunotherapy. Ultimately, however, overcoming inter-study heterogeneity and conducting rigorous functional validations remain imperative before their routine clinical integration. Keywords: hepatocellular carcinoma, tertiary lymphoid structures, formation mechanisms, imaging, prognosis