[Tertiary Lymphoid Structures as Predictive Biomarkers for Immune Checkpoint Inhibitor Therapy in Esophageal Cancer].

Abstract

While immune checkpoint inhibitors(ICIs)have dramatically improved treatment outcomes for esophageal cancer in recent years, substantial interpatient variability in therapeutic response remains a major clinical challenge. The development of reliable predictive biomarkers to identify patients likely to benefit from ICI therapy is thus an urgent priority. Conventional biomarkers such as programmed death‒ligand 1(PD‒L1)expression, tumor mutational burden(TMB), and microsatellite instability(MSI)have shown limited predictive utility and clinical applicability in esophageal cancer. These markers primarily reflect tumor‒intrinsic properties and may fail to capture the complex interplay between the tumor and its immune microenvironment. Tertiary lymphoid structures(TLS), ectopic lymphoid aggregates formed within the tumor microenvironment, have recently emerged as promising immune‒related biomarkers. TLS represent organized immune cell niches capable of facilitating local antigen presentation and adaptive immune activation. In this review, we provide an overview of key phase Ⅲ clinical trials of ICIs in esophageal cancer, with a particular focus on the biomarkers used in each study. We then summarize the structural and functional characteristics of TLS and highlight accumulating evidence supporting their value as predictive indicators of ICI efficacy. We further compare TLS with existing biomarkers, discussing the advantages and limitations of TLS assessment in clinical settings. Finally, we explore the future potential of TLS as both a biomarker and a therapeutic target, including the development of strategies aimed at promoting TLS formation to enhance anti‒tumor immunity. TLS offer a novel, immune microenvironment‒reflective dimension to patient stratification, and their integration into biomarker frameworks may refine personalized immunotherapy approaches for esophageal cancer.