Selective serotonin reuptake inhibitor fluoxetine, reduces solid tumor burden and metastasis through activation of host antitumor immune response and modulation of tumor microenvironment.

The tumor microenvironment (TME) plays a pivotal role in tumorigenesis, metastasis, and resistance to therapy. Although immunotherapeutic approaches such as CAR-T cells, immune checkpoint inhibitors, and tumor vaccines have demonstrated promising therapeutic effectiveness, tumor heterogeneity and immunosuppression continue to limit their efficacy in solid tumors, therefore, development of effective low-cost TME targeted therapy is necessary. Recent studies indicate, selective serotonin reuptake inhibitors display immune modulatory effects. Fluoxetine is an US Food and Drug Administration-approved selective serotonin reuptake inhibitor widely used in treatments of depression in patients with cancer, its effects toward immune responses in TME and effectiveness in management of solid tumor has not been explored previously. In this study, we investigated the immunoregulatory and antitumor effects of fluoxetine on solid tumor using syngeneic orthotropic B16-F10 melanoma and 4T1 breast carcinoma models in mice. Fluoxetine oral application significantly decreased the primary tumor burden and development of metastatic nodules. Histopathology, flowcytometry and confocal imaging revealed that fluoxetine significantly activates host antitumor immune system through increased cytotoxic interferon gamma secreting T cells and M1-macrophages accumulation at both primary and metastatic sites that results in elevated activated caspase-8 in cancer cells leading to immune mediated tumor cell death. Fluoxetine treatment led to decrease in immunosuppressive cells populations such as myeloid derived suppressor cells, M2-macrophages, regulatory T cells, while also reducing the level of cancer stemness markers and proteins associated with epithelia to mesenchymal transition and metastasis. Collectively, our study indicates the multifaceted role of fluoxetine in modulating the solid TME and highlight its potential in designing of novel anticancer treatment regimen. SIGNIFICANCE STATEMENT: Fluoxetine, an US Food and Drug Administration-approved selective serotonin reuptake inhibitor reduces solid tumor (breast and melanoma) load through immune mediated tumor cell death and restore antitumor immunity. It remodels tumor microenvironment, activates T cells, reduces cancer stemness and metastasis via regulation of epithelial mesenchymal transition factors, hypoxia Inducible factor 1α, and β-catenin.