3.2.4. Ptenpc−/−Smad4pc−/<sup>−</sup>

To examine a cooperative action of *Pten* and *Smad4* loss in PCa pathogenesis, De Pinho lab developed mice having prostate-specific genetic ablation of *Smad4* in Pten-null mice. These mice were highly aggressive and exhibited profound lymph node and pulmonary metastasis [45]. The importance of *Smad4* in PCa was further revealed by the development of metastatic and lethal PCa with 100% penetrance in *Smad4* and *Pten* double knockout mouse prostate [45]. *Ptenpc*−/−*Smad4pc*−/<sup>−</sup> has been used to analyze the efficacy of hypoxia-prodrug TH-302 and checkpoint blockade combination therapy. The combination of the hypoxia-prodrug and checkpoint blockade significantly extended the survival of *Ptenpc-*/*- Smad4pc-*/*-* mice [174]. Furthermore, Wang and colleagues utilized the *Ptenpc*−/−*Smad4pc*−/<sup>−</sup> mice model and identified that polymorphonuclear myeloid-derived suppressor cells (MDSCs) are one of the significant infiltrating immune cells in PCa and their depletion blocks PCa progression [175].
