Radiotherapy and tertiary lymphoid structures: balancing immune activation and immune damage in cancer immunotherapy
4 affiliations
- 1Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University
- 2Department of Pain Management, Cancer Center, West China Hospital, Sichuan University
- 3Department of Oncology, The First Affiliated Hospital of Chengdu Medical College
- 4National Key Laboratory for Shock Wave and Detonation Physics, Institute of Fluid Physics, China Academy of Engineering Physics
Abstract
Cancer immunotherapy, exemplified by immune checkpoint blockade (ICB), remains strongly influenced by the pre-existing immune organization of the tumor microenvironment. Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates whose density, maturation state, and spatial localization correlate with clinical prognosis and ICB response across several malignancies. Radiotherapy (RT) can reshape this immune context in opposing directions. By inducing immunogenic cell death, antigen release, cGAS-STING/type I interferon signaling, vascular remodeling, and lymphocyte recruitment, RT can create conditions that support TLS-associated antitumor immunity in selected settings. Conversely, high-dose or large-volume irradiation, poorly timed nodal exposure, and collateral injury to lymphocytes, tumor-draining lymph nodes, stromal scaffolds, and high endothelial venules can disrupt established TLSs or prevent their maturation. This review summarizes current evidence on the bidirectional relationship between RT and TLS biology, differentiating validated mechanisms from indirect evidence and hypothesis-generating translational concepts. We expound on how dose, fractionation, timing, irradiated volume, nodal management and radiation modality may influence antigen presentation, lymphocyte availability, and local immune architecture. Potential strategies such as lymph-node-aware planning, proton or heavy-ion therapy, FLASH RT, vascular normalization, STING or LTβR agonism, and ICB combinations are evaluated as investigational approaches rather than established TLS-directed clinical interventions. Future studies should evaluate whether optimized RT regimens can preserve or promote the functional maturation of TLSs, integrating paired tissue biopsies, spatial transcriptomics, advanced imaging, and circulating biomarkers to definitively correlate TLS remodeling with clinical outcomes. Graphical Abstract
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BibTeX
@article{zhang2026radiotherapy,
title = {{Radiotherapy and tertiary lymphoid structures: balancing immune activation and immune damage in cancer immunotherapy}},
author = {Yi Zhang and Hongshuai Li and Siyao Lv and Wenjun Meng and Jiamin Guo and Yating Lu and Lina Peng and Wu Chen and Wen Yang and Xingchen Peng},
journal = {Molecular Cancer},
year = {2026},
month = jul,
doi = {10.1186/s12943-026-02735-1},
url = {https://doi.org/10.1186/s12943-026-02735-1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Radiotherapy and tertiary lymphoid structures: balancing immune activation and immune damage in cancer immunotherapy
AU - Yi Zhang
AU - Hongshuai Li
AU - Siyao Lv
AU - Wenjun Meng
AU - Jiamin Guo
AU - Yating Lu
AU - Lina Peng
AU - Wu Chen
AU - Wen Yang
AU - Xingchen Peng
PY - 2026
DA - 2026/07/01
JO - Molecular Cancer
DO - 10.1186/s12943-026-02735-1
UR - https://doi.org/10.1186/s12943-026-02735-1
AB - Cancer immunotherapy, exemplified by immune checkpoint blockade (ICB), remains strongly influenced by the pre-existing immune organization of the tumor microenvironment. Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates whose density, maturation state, and spatial localization correlate with clinical prognosis and ICB response across several malignancies. Radiotherapy (RT) can reshape this immune context in opposing directions. By inducing immunogenic cell death, antigen release, cGAS-STING/type I interferon signaling, vascular remodeling, and lymphocyte recruitment, RT can create conditions that support TLS-associated antitumor immunity in selected settings. Conversely, high-dose or large-volume irradiation, poorly timed nodal exposure, and collateral injury to lymphocytes, tumor-draining lymph nodes, stromal scaffolds, and high endothelial venules can disrupt established TLSs or prevent their maturation. This review summarizes current evidence on the bidirectional relationship between RT and TLS biology, differentiating validated mechanisms from indirect evidence and hypothesis-generating translational concepts. We expound on how dose, fractionation, timing, irradiated volume, nodal management and radiation modality may influence antigen presentation, lymphocyte availability, and local immune architecture. Potential strategies such as lymph-node-aware planning, proton or heavy-ion therapy, FLASH RT, vascular normalization, STING or LTβR agonism, and ICB combinations are evaluated as investigational approaches rather than established TLS-directed clinical interventions. Future studies should evaluate whether optimized RT regimens can preserve or promote the functional maturation of TLSs, integrating paired tissue biopsies, spatial transcriptomics, advanced imaging, and circulating biomarkers to definitively correlate TLS remodeling with clinical outcomes. Graphical Abstract
SN - 1476-4598
ER -