Chronic stress‐induced brain‐derived small extracellular vesicles promote colorectal cancer through Treg differentiation

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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–adrenal (HPA) axis and sympathetic nervous system, yet the mechanisms by which psychological stress signals are transmitted from the central nervous system to the peripheral tumour immune microenvironment remain poorly understood. Brain‐derived small extracellular vesicles (BD‐sEVs), which can cross the blood–brain barrier, represent potential mediators of this neuroimmune crosstalk. 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‐acetate‐induced protein 1 (NOXA), which directly binds the mitochondrial chaperone heat shock protein 60 (HSP60) and inhibits its chaperone activity, triggering selective mtDNA release into the cytoplasm. Cytosolic mtDNA activates the cyclic GMP‒AMP synthase (cGAS)‒stimulator of interferon genes (STING)‒type I interferon (IFN‐I) pathway, driving Treg differentiation independently of the canonical myeloid cell leukaemia 1 (MCL‐1)‐dependent apoptotic pathway. Clinically, intratumoural CD4 + NOXA/Forkhead box P3 (FOXP3) expression correlates significantly with patient anxiety scores and predicts adverse survival outcomes. Conclusion Our study reveals an immunosuppressive ‘chronic stress‒BD‐sEV‒NOXA‒HSP60‒Treg’ axis and provides crucial mechanistic insights into the psychoneuroimmunological contributions to cancer progression and novel targets for therapeutic intervention. 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‐acetate‐induced protein 1 (NOXA) binds heat shock protein 60 (HSP60) and inhibits its chaperone activity, triggering mitochondrial DNA (mtDNA) release and activation of the cyclic GMP‒AMP synthase (cGAS)‒stimulator of interferon genes (STING) pathway to drive Treg differentiation. The stress‒BD‐sEV‒NOXA‒HSP60‒Treg axis is a key pathway that connects psychological stress with peripheral tumour immunosuppression. 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.

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