Ansofaxine suppressed NSCLC progression by increasing sensitization to combination immunotherapy

Introduction: Depression negatively impacts the prognosis of various cancers, including lung cancer, by influencing antitumor immune responses and impairing immune cell function. Antidepressants may modulate the tumor immune microenvironment, enhancing immunotherapy efficacy. However, the specific mechanisms remain unclear. This study investigates the effects of the antidepressant Ansofaxine on immune therapy in non- small cell lung cancer (NSCLC) mice with comorbid depression. Methods: Chronic unpredictable mild stress (CUMS) and Lewis lung cancer cells (LLC) model was established in mice. Ansofaxine and a combination of triple immunotherapy (anti-PD-1, anti-TNFR2, and anti-PTP1B) were treated in mice to monitor tumor growth and survival rates. Flow cytometry and immunohistochemistry were employed to analyze the dynamics of the immune system, while ELISA kits were used to quantify neurotransmitter levels. Results: Depression accelerated NSCLC progression, evidenced by increased tumor volume, spleen size, and reduced survival rates. Flow cytometry analysis demonstrated a reduction in the population of immune effector cells, with an increase in the proportion of immunosuppressive cells. Ansofaxine inhibited LLC cell proliferation and migration, enhancing apoptosis more effectively than venlafaxine and fluoxetine. Combined with triple immunotherapy, Ansofaxine improved survival rates and enhanced immune responses, increasing CD8+ T cell proportions and decreasing Tregs. Ansofaxine also restored serum serotonin and norepinephrine levels in depressed mice, reduced corticosterone, and decreased PD-L1 and TNFR2 expression in tumor tissues. Conclusion: The findings suggest that Ansofaxine may represent a promising therapeutic approach for NSCLC patients with comorbid depression, potentially enhancing both mental well-being and cancer-related outcomes.