Although psycho-social stress is a well-known factor that contributes to the development of cancer, it remains largely unclear whether and how environmental eustress influences malignant diseases and regulates cancer-related therapeutic responses. Using an established eustress model, we demonstrate that mice living in an enriched environment (EE) are protected from carcinogen-induced liver neoplasia and transplantable syngeneic liver tumors, owning to a CD8+ T cell-dependent tumor control. We identify a peripheral Neuro-Endocrine-Immune pathway in eustress, including Sympathetic nervous system (SNS)/β-adrenergic receptors (β-ARs)/CCL2 that relieves tumor immunosuppression and overcomes PD-L1 resistance to immunotherapy. Notably, EE activates peripheral SNS and β-ARs signaling in tumor cells and tumor infiltrated myeloid cells, leading to suppression of CCL2 expression and activation of anti-tumor immunity. Either blockade of CCL2/CCR2 or β-AR signaling in EE mice lose the tumor protection capability. Our study reveales that environmental eustress via EE stimulates anti-tumor immunity, resulting in more efficient tumor control and a better outcome of immunotherapy.

1. CKI -suppresses liver fibrosis and hepatocarcinogenesis in both preclinical and clinical studies. 2. CKI inhibits HSCs activation by stabilizing the interaction of Smad7/TGFβR1 to rebalance Smad2/Smad3 signaling, acting as an alternative approach to target TGF-β signaling.3. High expression of Smad7 and low expression of TGFβR1 in HCC tumors and surrounding normal liver tissues can be tumor suppressive.