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.