Saikosaponin A Alleviates Hepatocellular Carcinoma Growth Induced by Chronic Stress via Regulating Tumor Immune Microenvironment

Background: The tumor immune microenvironment is one of the main factors contributing to tumor metastasis, recurrence and drug resistance. Chronic stress is an important factor mediating the occurrence and progression of tumors by regulating tumor immune microenvironment. Saikosaponins have anti-stress and immunomodulatory effects. However, the therapeutic effects and mechanisms of Saikosaponins in chronic stress-induced tumor progression remain unclear. Aim: This study aimed to investigate the therapeutic effects of Saikosaponins on stress-induced tumor growth and further elucidate the underlying mechanisms. Methods: A mouse model was established using chronic restraint stress. The open field test was used to assess mouse behaviors. Stress hormone levels were measured by ELISA. The levels of cytokines and chemokines were measured by using Luminex. The proportions of T lymphocytes, monocytic-like myeloid-derived suppressor cells (mMDSC), granulocyte-like MDSC (gMDSC), and macrophages were measured by flow cytometry. A CCK8 assay was used to assess tumor cell proliferation. The expressions of adrenergic receptor and Ki67 were measured by immunohistochemistry. Propranolol and isoprenaline were used to investigate the underlying mechanisms. Results: First, we found that Saikosaponin A (SSA) reversed stress-induced depressive behavior. Second, SSA significantly inhibited hepatocellular carcinoma growth and reversed the stress-induced upregulation of Ki67 in tumor tissues. Furthermore, SSA reversed the changes of CD3 + CD4 + T lymphocytes, CD3 + CD8 + T lymphocytes, M2 macrophages, gMDSC and mMDSC induced by chronic restraint stress. Mechanistically, SSA decreased norepinephrine (NE) levels and reduced the expression of β 2 adrenergic receptor in chronically stressed mice. Finally, we found that SSA inhibited hepatocellular carcinoma growth and reversed tumor immune microenvironment alterations in stressed mice by blocking β-adrenergic signaling. Conclusion: Our results suggested that SSA inhibits hepatocellular carcinoma growth by blocking β-adrenergic signaling, thereby enhancing the anti-tumor immune response. Our study provides new insights into the importance of the psychological neuroendocrine immune intervention in the treatment of hepatocellular carcinoma. The image depicts two panels on chronic stress’s impact on tumor growth. Left panel: Chronic stress raises norepinephrine levels, reducing CD3+CD4+ and CD3+CD8+ T cells in blood, while increasing granulocytic and monocytic myeloid-derived suppressor cells. Tumor shows similar changes with increased Ki67 and beta 2 adrenergic receptor, causing hepatocellular alterations. Right panel: Chronic stress with somatostatin analog treatment boosts CD3+CD4+ and CD3+CD8+ T cells in blood, reducing suppressor cells. Tumor sees increased CD3+CD4+ and CD3+CD8+ T cells, decreased suppressor cells, impacting carcinoma growth.Diagram showing chronic stress effects on tumor growth with immune cell changes in blood and tumor compartments.