Modulating phosphodiesterase-5 activity to suppress the immunosuppressive mechanisms of myeloid-derived suppressor cells in breast cancer
Abstract
Phosphodiesterase-5 (PDE5) inhibitors have been shown to have potential as an adjuvant therapy for cancer. Tadalafil is a potent and selective PDE5 inhibitor that has been shown to inhibit the aggregation of myeloid-derived suppressor cells (MDSC) within tumors. Given the pivotal role of STAT3 signaling in mediating MDSC immunosuppression, we investigated the impact of tadalafil on MDSC differentiation and inhibitory function. Our findings indicate that tadalafil significantly attenuates in situ breast tumor growth and metastasis while impairing the capacity of MDSCs to suppress T-cell proliferation, concomitant with reduced STAT3 phosphorylation. Transcriptomic analysis revealed that tadalafil modulates MDSC metabolism, upregulates NAD+ nucleotidase activity, and disrupts chemotaxis-related transcriptional programs, including downregulation of key chemokine receptors. Consistent with these observations, in vitro migration assays confirmed tadalafil-mediated inhibition of MDSC chemotaxis toward tumor cells. Furthermore, tadalafil markedly enhanced nuclear PARP1 expression, which exhibits a negative regulatory relationship with STAT3. Collectively, these data demonstrate that tadalafil exerts systemic and local immunomodulatory effects on MDSCs during tumor infiltration, primarily through PARP1-STAT3 axis regulation. These insights underscore the therapeutic potential of tadalafil in reprogramming MDSC-mediated immunosuppression in cancer.
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