Chronic stress-induced brain-derived small extracellular vesicles promote colorectal cancer through Treg differentiation.
Overview
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Laboratory, Ganzhou People's Hospital, Ganzhou, China
- Department of Gynaecology, Ganzhou People's Hospital, Ganzhou, China
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Clinical Pharmacology Research Center, Peking Union Medical College Hospital, State Key Laboratory of Complex Severe and Rare Diseases, NMPA Key Laboratory for Clinical Research and Evaluation of Drug, Beijing Key Laboratory of Clinical PK & PD Investigation for Innovative Drugs, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Guangzhou, China
Abstract
Background: Chronic stress is increasingly recognised as a risk factor for poor prognosis in colorectal cancer (CRC) through sustained activation of the hypothalamic–pituitary–a
Methods: A chronic restraint stress (CRS) mouse model was established in both subcutaneous (MC38) and orthotopic (CT26) CRC models. BD‐sEVs were enriched from plasma using anti‐L1 cell adhesion molecule (L1CAM) antibodies and characterised by transmission electron microscopy and nanoparticle tracking analysis. Multichannel flow cytometry was used to analyse immune cell populations in the tumour microenvironment. Mechanistic studies included microRNA (miRNA) sequencing, single‐cell RNA sequencing, co‐immunoprecipitation, mass spectrometry, mitochondrial function assessment and mitochondrial DNA (mtDNA) detection. Clinical validation was performed in a retrospective cohort (n = 67) and a prospective cohort (n = 37) of CRC patients, with anxiety levels assessed by the Hamilton Anxiety Rating Scale (HAMA).
Results: We show that chronic stress‐activated brain regions remodel the miRNA cargo of circulating BD‐sEVs, which are taken up by CD4+ naïve T cells within the tumour microenvironment, promoting regulatory T‐cell (Treg) differentiation and immunosuppressive function. Mechanistically, stress‐responsive miRNAs (miR‐342‐3p, miR‐15a‐5p and miR‐381‐3p) upregulate phorbol‐12‐myristate‐13‐
Conclusion: Our study reveals an immunosuppressive ‘chronic stress‒BD‐sEV‒NOXA‒HSP60
Key points: Chronic stress promotes the differentiation of regulatory T cells (Treg) in the tumour microenvironment through brain‐derived small extracellular vesicles (BD‐sEVs) to inhibit antitumour immunity.
Mechanistically, BD‐sEV‐induced phorbol‐12‐myristate‐13‐
The stress‒BD‐sEV‒NOXA‒HSP60
The expression of NOXA and Forkhead box P3 (FOXP3) in clinical tumour samples correlates with the level of anxiety and may serve as potential prognostic biomarkers.
Reproduced under the paper's license (CC BY), from the paper cited above.
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Data
Datasets cited
- geo:GSE108989 — at NCBI GEO; found in the text, “Single‐cell RNA sequencing data acquisition…”
Data availability statement
The proteome resources data reported in this paper have been deposited in the iProX (National Center for Protein Sciences, Beijing, China) (https://
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
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Version 1, 27 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 12 authors, 5 keywords, 13 MeSH terms, 6 funders, 57 references.
Cite
This paper
Ni, H., Ling, Y., Tang, T., Liu, Y., Chai, Z., Qing, S., Xiao, X., Ding, Q., Zhao, D., Pan, H., Lin, Y., & Wu, D. (2026). Chronic stress-induced brain-derived small extracellular vesicles promote colorectal cancer through Treg differentiation. Clinical and translational medicine, 16(8), e70756. https://
BibTeX
@article{ni2026chronic,
author = {Ni, Huanhe and Ling, Yunyan and Tang, Ting and Liu, Yuyang and Chai, Zhen and Qing, Shunjie and Xiao, Xujie and Ding, Qiqiong and Zhao, Dandan and Pan, Hui and Lin, Yan and Wu, Dehua},
title = {{Chronic stress-induced brain-derived small extracellular vesicles promote colorectal cancer through Treg differentiation}},
journal = {Clinical and translational medicine},
year = {2026},
month = aug,
volume = {16},
number = {8},
pages = {e70756},
publisher = {Wiley},
issn = {2001-1326},
doi = {10.1002/
url = {https://
pmid = {42625444},
pmcid = {PMC13494519}
}
RIS
TY - JOUR
AU - Ni, Huanhe
AU - Ling, Yunyan
AU - Tang, Ting
AU - Liu, Yuyang
AU - Chai, Zhen
AU - Qing, Shunjie
AU - Xiao, Xujie
AU - Ding, Qiqiong
AU - Zhao, Dandan
AU - Pan, Hui
AU - Lin, Yan
AU - Wu, Dehua
TI - Chronic stress-induced brain-derived small extracellular vesicles promote colorectal cancer through Treg differentiation
T2 - Clinical and translational medicine
J2 - Clin Transl Med
PY - 2026
DA - 2026/
VL - 16
IS - 8
SP - e70756
SN - 2001-1326
PB - Wiley
DO - 10.1002/
UR - https://
LA - en
ER -
CSL-JSON
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