Repurposing the SSRI paroxetine increases lymphocyte mobilization and improves the efficacy of measles virus-based...

Glioblastoma (GBM) is the most common primary malignant brain tumor, with a poor prognosis and limited response to immunotherapy. Systemic immunosuppression in GBM is a significant challenge partly driven by T cell sequestration in the bone marrow via sphingosine-1-phosphate receptor 1 (S1P1) internalization by G protein-coupled receptor kinase 2 (GRK-2). We demonstrated that immunovirotherapy based on oncolytic measles virus armed with the neutrophil-activating protein (MV-s-NAP), combined with anti-PD-1 and anti-TIGIT, increases S1P1 expression on bone marrow lymphocytes. Furthermore, repurposing paroxetine, one of the Food and Drug Administration-approved selective serotonin reuptake inhibitors (SSRIs) with GRK-2 inhibitory action, enhanced this effect, leading to greater lymphocyte circulation, activation, and improved survival in an orthotopic syngeneic mouse model. By overcoming key mechanisms of immune suppression and repurposing a widely available, clinically safe drug, this strategy represents a highly translatable approach to enhancing the efficacy of immunovirotherapy for gliomas.