Extracellular vesicles derived from irradiated tumor cells foster immunosuppressive macrophages formation to promote esophageal squamous cell carcinoma immune evasion

Sep 30, 2026

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Radiotherapy remodels the tumor microenvironment, where tumor-associated macrophages (TAMs) drive immunosuppression; however, the mechanism by which radiotherapy programs TAMs toward a PD-L1+ phenotype is unclear. ESCC xenografts in immunodeficient mice were exposed to localized radiotherapy or sham, followed by quantification of PD-L1+ TAMs and characterization of extracellular vesicles (EVs) from irradiated ESCC cells. EV-educated macrophages suppressed CD8+ T-cell proliferation and cytokine/granzyme responses. DYNLL1-AS1-enriched EVs activated PD-L1 transcription via SEC22B/FOXP1 signaling, counteracting PD-L1 blockade and correlating with poor survival in patients.

LanguageEnglish

CategoryHealthcare

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Abstract

Introduction

Ivyspring International Publisher InternationalJournal of Biological Sciences 2026; 22(2): 802-822. doi: 10.7150/ijbs.123646 Research Paper Extracellular vesicles derived from irradiated tumor cells foster immunosuppressive macrophages formation to promote esophageal squamous cell carcinoma immune evasion Shanshan Jiang\#1,2,3,4,5,6, Yechun Pang\#1,2,3,4,5, Yue Zhou\#1,2,3,4,5, Jianjiao Ni1,2,3,4,5, Li Chu1,2,3,4,5, Xiao Chu1,2,3,4,5, Jianghong Zhang7, Yan Pan7, Yida Li8, Ruiting Ye1,2,3,4,5, Hongru Chen1,2,3,4,5, Silai Yu1,2,3,4,5, Tiantian Guo1,2,3,4,5, Chunlin Shao7􀀍, Xi Yang1,2,3,4,5􀀍, Zhengfei Zhu1,2,3,4,5􀀍 1. Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China. 2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. 3. Shanghai Clinical Research Center for Radiation Oncology, China. 4. Shanghai Key Laboratory of Radiation Oncology, Shanghai 200032, China. 5. Institute of Thoracic Oncology, Fudan University, Shanghai 200032, China. 6. Department of Radiotherapy, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Cancer Hospital of Dalian University of Technology, Shenyang, 110042, Liaoning, China. 7. Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai, China. 8. The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, China. \# Shanshan Jiang, Yechun Pang and Yue Zhou contributed equally to this work. 􀀍 Corresponding authors: Zhengfei Zhu, Department of Radiation Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China. Phone: +86-18017312901, Fax: +86-2164175242. E-mail: [fuscczzf@163.com. Xi Yang](fuscczzf@163.com. Xi Yang), Department of Radiation Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China. Phone: +86-021-65642662, Fax: +86-2164175242. E-mail: [ntgeorge@qq.com. Chunlin Shao](ntgeorge@qq.com. Chunlin Shao), Institute of Radiation Medicine, Shanghai Medical College, Fudan University, No. 2094 Xie-Tu Road, Shanghai, 200032, China. E-mail: [clshao@shmu.edu.cn](clshao@shmu.edu.cn). © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License ([https://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/)). See [https://ivyspring.com/terms](https://ivyspring.com/terms) for full terms and conditions. Received: 2025.08.13; Accepted: 2025.11.29; Published: 2026.01.01 Abstract Background: Radiotherapy (RT) remodels the tumor microenvironment (TME) . Tumor-associated macrophages (TAMs) are key mediators of TME, yet how RT reprograms TAMs toward a programmed death ligand- 1(PD-L1)⁺ immunosuppressive phenotype remains unclear. Materials and Methods: Esophageal squamous cell carcinoma (ESCC) subcutaneous xenografts in immunodeficient mice received localized RT or sham treatment. Tumor-infiltrating PD-L1⁺ TAMs were quantified via multiplex immunofluorescence and flow cytometry. Extracellular vesicles (EVs) derived from irradiated ESCC cells (IR-EVs) were isolated and characterized by nanoparticle tracking analysis and transmission electron microscopy. Functional assays included co-culture of IR-EVs-educated macrophages with autologous CD8⁺ T cells. RNA sequencing identified DYNLL1-AS1 as the most upregulated lncRNA in IR-EVs. Mechanistic studies employed RNA pull-down, mass spectrometry, RNA immunoprecipitation, and dual-luciferase reporter assays. Clinical validation utilized ESCC specimens for RNA in situ hybridization. Prognostic significance was assessed via Kaplan-Meier and Cox regression analyses. Results: RT triggered ESCC cells to secrete DYNLL1-AS1-enriched EVs, which reprogrammed macrophages into PD-L1⁺ immunosuppressive TAMs. IR-EVs-educated macrophages suppressed CD8⁺

FAQs

How does radiotherapy affect tumor-associated macrophages in this study?

Radiotherapy induces ESCC cells to release DYNLL1-AS1-enriched extracellular vesicles that reprogram macrophages into PD-L1+ immunosuppressive TAMs.

What role do extracellular vesicles (EVs) derived from irradiated tumor cells play?

IR-EVs educate macrophages to suppress CD8+ T-cell proliferation and IFN-γ/Granzyme B secretion, promoting immune evasion and tumor growth.

Which molecular pathway links DYNLL1-AS1 to PD-L1 expression?

DYNLL1-AS1 binds SEC22B, enabling interaction with FOXP1 to activate PD-L1 transcription through promoter binding.

Sep 30, 2026

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