Environmental eustress modulates β-ARs/CCL2 axis to induce anti-tumor immunity and sensitize immunotherapy against liver cancer in mice

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)/beta-adrenergic receptors (beta-ARs)/CCL2 that relieves tumor immunosuppression and overcomes PD-L1 resistance to immunotherapy. Notably, EE activates peripheral SNS and beta-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 beta-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. The impact of positive environment stimulations (eustress) on cancer biology remains poorly understood. Here the authors show that exposure to an environment enrichment stimulates anti-tumor immunity and reduces tumor growth in preclinical models of liver cancer.

Automated summary

Positive environmental stimuli through activating anti-tumor immunity lead to more effective tumor control and improved outcomes of immunotherapy in preclinical models of liver cancer. The impact of positive environment stimulations on cancer biology remains poorly understood.