2. Academic Validation
  3. Modulating phosphodiesterase-5 activity to suppress the immunosuppressive mechanisms of myeloid-derived suppressor cells in breast cancer

Modulating phosphodiesterase-5 activity to suppress the immunosuppressive mechanisms of myeloid-derived suppressor cells in breast cancer

  • Breast Cancer Res. 2025 Oct 23;27(1):184. doi: 10.1186/s13058-025-02131-5.
Yingxue Guo # 1,  Mengyun Chen # 2,  Qi Yuan # 2,  Jie Huang 3,  Wen Mao 4,  Xianli Liu 5,  Lu Jin 1,  Lijia Chen 2,  Jingyi Lou 2,  Xia Liu 1,  Qi Pan 6,  Huiying Fu 7 8,  Qiyang Shou 9 10
Affiliations

Affiliations

  • 1 The Second Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Jinhua Academy, Hangzhou, 310053, Zhejiang, China.
  • 2 School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China.
  • 3 The First Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310053, Zhejiang, China.
  • 4 Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Taizhou, 317000, Zhejiang, China.
  • 5 The First Hospital of Jiaxing, Jiaxing, 314000, Zhejiang, China.
  • 6 Wenling TCM Hospital Affiliated to Zhejiang Chinese Medical University, Wenling, 317500, Zhejiang, China. wlpanqi@163.com.
  • 7 The Second Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Jinhua Academy, Hangzhou, 310053, Zhejiang, China. fhy131@126.com.
  • 8 School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China. fhy131@126.com.
  • 9 The Second Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Jinhua Academy, Hangzhou, 310053, Zhejiang, China. sqy133@126.com.
  • 10 School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China. sqy133@126.com.
  • # Contributed equally.
PMID: 41131545 DOI: 10.1186/s13058-025-02131-5
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.

Keywords

Breast cancer; Immunosuppression; Myeloid-derived suppressor cells; Phosphodiesterase type 5 inhibitor; Tumor microenvironment.

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