Research progress of tertiary lymphoid structure in hepatocellular carcinoma: from prognostic biomarkers to new strategies for immunotherapy

Tertiary lymphoid structures (TLS) are important ectopic immune aggregates that develop within the tumor microenvironment (TME) of hepatocellular carcinoma (HCC) and have attracted increasing attention due to their potential clinical value. Recent studies have identified TLS as key players in prognosis assessment and immunotherapy response prediction in HCC, with their maturity and spatial distribution being critical determinants of clinical outcomes. TLS can be classified into intratumoral and peritumoral types, which exhibit distinct predictive values; the clinical significance of peritumoral mature TLS remains controversial. Histopathological analysis remains the gold standard for detecting TLS structure and composition. In recent years, predictive models based on CT/MRI radiomics and machine learning have achieved promising progress in non-invasive detection. This review summarizes and analyzes the formation mechanism of TLS in HCC, emphasizes their structural characteristics, spatial distribution, clinical value, and detection methods, presents current challenges and research directions, and provides a new perspective for the diagnosis and treatment of HCC.