Selective Serotonin Reuptake Inhibitor Fluoxetine Alters Gene Expression Patterns of Sarcoma and Significantly Reduces Tumor Load through Modulation of the Tumor Microenvironment and Restoration of the Host Antitumor Immune System

The effectiveness of cancer therapy is significantly hindered by immunosuppressive mechanisms within the tumor microenvironment (TME). Immunotherapy for cancer leverages the body’s immune system, Enhanced immune response to identify, attack, and eliminate tumor cells is the primary goal of immunotherapy. Immune checkpoint blocking, adoptive cell therapy, and cytokine and monoclonal antibody treatments have been reported to achieve significant success in cancer therapy. However, their effectiveness may vary, and immune-related side effects remain a major challenge. In this study, we evaluated the immunomodulatory properties of the selective serotonin reuptake inhibitor (SSRI) fluoxetine. It has been previously reported that fluoxetine exhibits anti-inflammatory properties and has limited effects against cancer; however, a detailed systematic study of the effects of fluoxetine on tumor growth, survival, and the host immune system has not been undertaken. This study evaluates the therapeutic potential of fluoxetine in sarcoma-bearing animals and explores the underlying mechanisms of action. Fluoxetine treatment in vitro showed minimal effects on sarcoma proliferation or survival; however, microarray-based gene expression analysis revealed the induction of a number of genes and pathways related to immune regulations in fluoxetine-treated sarcoma cells. These findings are consistent with the results of our in-silico analysis of fluoxetine target genes in myeloid lineage cells in the TME. Treatment with fluoxetine significantly reduced tumor burden in vivo . The observed antitumor effects were driven by modulation of the tumor microenvironment, including reduced the immunosuppressive properties of myeloid lineage cells and restored the number and activation of cytotoxic T cells. These findings demonstrate fluoxetine as a potential novel adjunct therapy for cancer, worthy of further preclinical and clinical investigations.