Tertiary lymphoid structures (TLS): The mechanism hub and therapeutic target of neoadjuvant immunotherapy for...

The causal involvement of tertiary lymphoid structures (TLS) in the context of neoadjuvant immunotherapy for hepatocellular carcinoma (HCC) remains inadequately defined, and a comprehensive clinical translation framework is currently absent. This review addresses two primary questions: (1) Does the formation of TLS causally influence the efficacy of immunotherapy? (2) What strategies can facilitate the clinical implementation of TLS? A systematic literature search was conducted using PubMed and Web of Science databases, covering all relevant peer-reviewed studies up to March 2026, focusing on TLS in HCC neoadjuvant immunotherapy. Key quantitative findings indicate that responders exhibit an enrichment of intratumoral TLS; a high density of TLS is associated with a 100% recurrence-free survival rate at 30 months; surgical patients demonstrate a major pathological response rate of 33.3% and an overall survival rate of 86% at four years. Furthermore, experimental depletion of B cells in murine HCC models abolishes antitumor efficacy, thereby establishing TLS as a causal mediator in preclinical settings. These findings are integrated into a conceptual framework describing the intratumoral immune cycle, and a clinical roadmap is proposed, which includes standardized TLS detection methods (hematoxylin-eosin-saffron staining combined with CD20/CD23 immunohistochemistry) and potential TLS-targeting therapeutic strategies. This review provides oncologists and researchers with an evidence-based framework to incorporate TLS into precision neoadjuvant immunotherapy for HCC, advancing the field from mere associative observations to establishing causality and transitioning TLS from a biomarker to a therapeutic target.