Tertiary lymphoid structures in cancer: their development, composition, clinical prognosis, and the drivers of the anti-tumor responses

Sep 22, 2026

Tertiary lymphoid structures (TLS) are ectopic lymphoid aggregates formed in chronic inflammatory tumor microenvironments. Clinical cohorts across solid cancers show that mature TLS with intact germinal centers act as independent favorable prognostic biomarkers and predict improved responses to immune checkpoint inhibitors. Yet heterogeneity in maturity, spatial localization, and cellular composition can yield dual tumor-promoting or tumor-suppressing effects. In this review, TLS development, molecular drivers, stromal licensing, standardized detection methods, and translational value are integrated, alongside mechanistic and therapeutic strategies and barriers to clinical translation.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages21

Reading Time53 min

AccessFree to download

Abstract

Introduction

Structural and functional features of TLS

TLS roles in tumors and therapeutic responses

Dou et al. Molecular Biomedicine (2026) 7:159 [https://doi.org/10.1186/s43556-026-00562-w](https://doi.org/10.1186/s43556-026-00562-w) Molecular Biomedicine REVIEW Open Access Tertiary lymphoid structures in cancer: their development, composition, clinical prognosis, and the drivers of the anti-tumor responses Zhi‑chao Dou 1†, Yu‑chao Shi2†, Kun Meng3†, Jia‑Rong Wang1, Xin‑hua Liang4* andYa‑Ling Tang1* Abstract Tertiary lymphoid structures (TLS) are ectopic lymphoid aggregates formed under chronic inflammatory tumor microenvironments. Clinical cohorts across solid cancers demonstrate that mature TLS with intact germinal centers serve as independent favorable prognostic biomarkers and predict superior responses to immune checkpoint inhibi‑ tors. However, the differences in maturity, spatial localization and cellular composition of TLSs result in heterogeneity in their immunostimulation or immunosuppression, thereby exhibiting dual functions of promoting or anti‑tumor. Furthermore, there are significant differences in the maturity assessment methods and definitions of TLS, which jointly hinder the clinical evaluation and targeted treatment of TLSs. In this review, we integrate current understanding of TLS development, molecular drivers, and stromal licensing, and dissect the key mechanisms by which TLS contribute to anti‑tumor immunity within tumors. We consolidate standardized TLS detection methods encompassing pathol‑ ogy, multi‑omics, and radiogenomics, and further explore the translational value ofTLS maturation status, germinal center‑like responses, and intratumoral versus peritumoral localization in prognosis and immune checkpoint block‑ ade. We systematically elaborate therapeutic strategies for inducing functional TLS, dissect the intrinsic mechanisms by which TLS synergistically boost the efficacy of adoptive cell therapy and tumor vaccines, and outline major bottle‑ necks hindering clinical translation. Collectively, this work constructs a comprehensive multi‑dimensional framework for TLS research and provides actionable insights to develop TLS‑targeted immunotherapies for human cancers. Keywords Tertiary lymphoid structures, Tumor microenvironment, Antitumor immunity, Immune checkpoint inhibitors, Prognostic biomarker, Immunotherapy †Zhi‑chao Dou, Yu‑chao Shi and Kun Meng contributed equally to this work. *Correspondence: Xin‑hua Liang [lxh88866@scu.edu.cn](lxh88866@scu.edu.cn)[ ](lxh88866@scu.edu.cn)Ya‑Ling Tang [tangyaling@scu.edu.cn](tangyaling@scu.edu.cn) 1 State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases &, Department of Oral Pathology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China 2 State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases &, Department of Oral Medical Imaging, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China 3 Department of Stomatology, The General Hospital of Western Theater Command PLA, Chengdu, China 4 State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases &, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China © The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use

FAQs

What are tertiary lymphoid structures (TLS) and where do they form in cancer?

TLS are ectopic lymphoid aggregates that arise in non-lymphoid tissues under persistent inflammation, commonly forming within tumors and in adjacent stromal compartments.

Why do TLS have both pro-tumor and anti-tumor effects?

Differences in TLS maturity, spatial localization, and cellular composition create heterogeneity, leading to either immunostimulation or immunosuppression.

How are mature TLS linked to prognosis and immune checkpoint therapy?

Mature TLS with intact germinal centers serve as independent favorable prognostic biomarkers and predict superior responses to immune checkpoint inhibitors.

Sep 22, 2026

Upload by CatatanPagi