Mammary tumors-derived exosomes induce striatal NF-κB signaling, microglial reactivity, and anxiety/depression-like behaviors.

Emerging evidence links peripheral cancer growth with affective disturbances, yet the mechanisms bridging tumor biology and central dysfunction remain poorly defined. In a cohort of newly diagnosed breast cancer patients and healthy controls, patients exhibited elevated depressive and anxiety-related symptoms, accompanied by a focal reduction of amplitude of low-frequency fluctuations (ALFF) in the right caudate. The ALFF of right caudate is negatively correlated with individual affective scores, suggesting early striatal involvement in cancer-related affective vulnerability. Building on these observations, we used mammary tumor-bearing mouse models and found that mammary tumor-bearing mice developed pronounced anxiety/depression-like behaviors accompanied by microglial reactivity and heightened NF-κB signaling in the striatum. In vitro, exosomes isolated from mammary tumor-bearing cells activated BV-2 microglia and the NF-κB pathway, and enhanced pro-inflammatory cytokine production. Systemic administration of tumor cell-derived exosomes in naïve mice reproduced both behavioral abnormalities and striatal microglial/NF-κB activation, whereas pharmacological inhibition of exosome release in mammary tumor-bearing mice ameliorated behavioral abnormalities and reduced neuroinflammation. Together, these human and experimental data identify exosomes as a mechanistic conduit linking peripheral malignancy to central affective pathology. Exosome-driven NF-κB activation in striatal microglia emerges as a key driver of cancer-associated anxiety and depression. It represents a potential therapeutic point for mitigating neuropsychiatric comorbidity in cancer.